Expression and significance of Ang-2/Ang-1 in the vitreous of patients with proliferative diabetic retinopathy

Expression and significance of Ang-2/Ang-1 in the vitreous of patients with proliferative diabetic retinopathy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Expression and significance of Ang-2/Ang-1 in the vitreous of patients with proliferative diabetic retinopathy Xiang Ma, Li-li Nie, Bo Jia, Yi-chun Yu, Yu-xun Zhao, Yan Cheng This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4238976/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose To explore the significance of the Ang-2/Ang-1 ratio and VEGF expression in the vitreous of PDR patients. Methods A total of 50 PDR patients were enrolled in this study, including 25 who received intravitreal conbercept injection and 25 who did not. The control group consisted of 10 patients with macular holes. Vitreous samples were collected after vitrectomy for determination of Ang-1, Ang-2 and VEGF expression levels by enzyme-linked immunosorbent assay. Results The vitreous expression of Ang-1, Ang-2, and VEGF and the Ang-2/Ang-1 expression ratio were significantly greater in the PDR group than in the control group (P < 0.05). The expression of Ang-2 and the Ang-2/Ang-1 expression ratio in the vitreous of the active PDR group were significantly greater than those of the inactive PDR group administered injection and the PDR group without injection. There was a significant positive correlation between the Ang-2/Ang-1 expression ratio and the vitreous expression of VEGF in the PDR group without injection (correlation coefficient: 0.843, P < 0.001). Conclusions The increased Ang-2/Ang-1 expression in the vitreous of PDR patients suggest that Ang-2/Ang-1 and VEGF expression are associated with angiogenic activity in PDR. Health sciences/Diseases Health sciences/Medical research Health sciences/Molecular medicine Health sciences/Pathogenesis Health sciences/Risk factors angiopoietin-1 angiopoietin-2 vascular endothelial growth factor proliferative diabetic retinopathy angiopoietin-2/angiopoietin-1 Introduction Diabetic retinopathy (DR), which is characterized by progressive retinal microangiopathy caused by chronic hyperglycemia, is the leading cause of irreversible visual impairment in diabetic patients. Moreover, DR has become the most common cause of blindness among the working-age population in developed countries and seriously affects the quality of life of diabetic patients. According to the International Guidelines for Clinical Diabetic Retinopathy, DR can be divided into nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR). The earliest visible clinical signs of NPDR are microhemorrhages and microaneurysms, which represent damage to retinal capillaries [ 1 ] . PDR is the most serious complication of DR, and 50% of untreated PDR patients develop irreversible blindness within 5 years of diagnosis [ 2 ] . Multiple mechanisms contribute to vision loss in DR, including metabolic changes [ 3 , 4 ] , coagulation and hemodynamic disorders [ 5 , 6 ] , hypoxia and oxidative stress [ 7 , 8 ] , and microvascular activation due to a variety of proangiogenic cytokines [ 9 ] . Accumulating evidence has revealed several angiogenic factors that may contribute to the progression of DR, such as vascular endothelial growth factor [ 4 , 10 ] , basic fibroblast growth factor [ 11 , 12 ] , insulin-like growth factor [ 13 ] , tumor necrosis factor-α [ 14 ] , interleukin-1ß [ 15 ] , angiopoietin [ 16 ] , hepatocyte growth factor [ 17 ] , monocyte chemoattractant protein-1 [ 18 ] and platelet-derived growth factor [ 19 ] , the expression of which have been detected in the vitreous of PDR patients. These angiogenic factors lead to increased retinal vascular permeability, apoptosis, vascular inflammation, chronic retinal hypoxia, and extensive retinal ischemia, ultimately leading to retinal neovascularization. Among these cytokines, the proangiogenic effect of VEGF in PDR has been confirmed by many clinical studies, and VEGF plays a key role in the development of DR [ 20 , 21 ] . The discovery of VEGF and the subsequent demonstration that VEGF expression is spatially and temporally restricted to regions of vascular development show that it is the driving force for developmental angiogenesis and ischemic/hypoxic regulation of retinal vessels. In addition, there was a significant correlation between increased VEGF expression in the vitreous and the severity of DR [ 22 , 23 ] . As a pathogenic factor of abnormal growth and leakage of retinal blood vessels, VEGF has been deemed a therapeutic target for DR. The treatment of retinal and choroidal vascular diseases was revolutionized in the first decade of the 21st century with the introduction of VEGF blockers, which have significantly improved the prognoses of patients with these diseases, as well as preventing or even reversing PDR and DME. In addition to VEGF and the VEGF receptor system, the Ang/Tie-2 pathway constitutes another recently identified endothelial cell-specific ligand‒receptor system that is critical not only for vascular development but also for postnatal angiogenesis. Ang-1 is a potent agonist of Tie-2. Activated Tie-2 increases endothelial cell survival, adhesion, stability and endothelial barrier function and maintains the structural integrity of mature blood vessels and stabilizes the vasculature [ 24 , 25 ] . Thus, Ang-1 expression prevents vascular leakage and pathological growth of abnormal vessels and attenuates proinflammatory responses in endothelial cells [ 26 ] . Ang-2 is a partial agonist or antagonist of Tie-2, acting as a competitive inhibitor of Ang-1 binding and ultimately leading to vascular dysfunction [ 27 ] . In many pathological conditions, the balance of expression of the two angiopoietins is disrupted, and Ang-2 expression is relatively increased. Ang-2 expression leads to the progression of a variety of vascular diseases through an increase in vascular permeability and a pathological increase in instability [ 26 , 28 , 29 ] . Because of the role of Ang/Tie-2 signaling in maintaining vascular homeostasis and the upregulation of Ang-2 expression in retinal and choroidal diseases [ 30 , 31 ] , novel therapies targeting this pathway may reduce the vascular instability associated with neovascularization. In this study, the expression of Ang-1, Ang-2 and VEGF in the vitreous of 60 patient samples (50 from PDR patients and 10 from macular hole patients) were measured by ELISA to explore the changes in and significance of changes in the Ang-2/Ang-1 expression ratio and VEGF expression in the vitreous of patients with PDR. Results Patient characteristics As shown in Table 1 , there was no significant difference in the affected eye, disease duration or preoperative intraocular pressure between the PDR group and the control group (P > 0.05). There were significant differences in age, sex, history of diabetes, history of hypertension, duration of operation and whether injection was performed (P < 0.05). Differences in the concentrations of three cytokines and the Ang-2/Ang-1 expression ratio between the PDR group and the control group As shown in Table 2 , the Ang-1 concentration was 37.66 ± 45.71 (pg/ml) in the PDR group and 2.33 ± 14.7 (pg/ml) in the control group, which was significantly lower than that in the PDR group (P < 0.05). The Ang-2 concentration was 744.87 ± 747.80 (pg/ml) in the PDR group and 0.14 ± 43.45 (pg/ml) in the control group, which was significantly lower than that in the PDR group (P < 0.001). The VEGF level in the PDR group was 123.72 ± 294.14 (pg/ml) and was lower than the minimum detection range of the ELISA in the control group, which was significantly lower than that in the PDR group (P < 0.001). The ratio of Ang-2/Ang-1 was 16.66 ± 32.92 (pg/ml) in the PDR group and 0.36 ± 7.36 (pg/ml) in the control group, which was significantly lower than that in the experimental group (P < 0.05). Analysis of the three cytokines and Ang-2/Ang-1 ratios in the active PDR group and the inactive PDR group As shown in Table 3 , in the injection group, the concentration of Ang-1 in the active PDR group was lower than that in the inactive PDR group (4.99 ± 29.21 pg/ml vs. 56.96 ± 51.74 pg/ml; P < 0.05), the concentration of Ang-2 was greater than that in the inactive PDR group (1226.11 ± 950.43 pg/ml vs. 475.22 ± 308.16 pg/ml; P < 0.05), and the ratio of Ang-2/Ang-1 was greater than that in the inactive PDR group (49.92 ± 39.67 pg/ml vs. 14.55 ± 12.65 pg/ml; P 0.05). As shown in Table 4 , in the noninjected group, the concentration of Ang-2 in the active PDR group was greater than that in the inactive PDR group (1099.43 ± 597.65 pg/ml vs. 337.80 ± 188.76 pg/ml; P < 0.05), the concentration of VEGF was greater than that in the inactive PDR group (445.24 ± 490.32 pg/ml vs. 134.74 ± 166.85 pg/ml; P < 0.05), and the ratio of Ang-2/Ang-1 was greater than that in the inactive PDR group (23.32 ± 13.52 pg/ml vs. 8.55 ± 9.26 pg/ml; P 0.05). Analysis of the three cytokines and the Ang-2/Ang-1 ratio in the hypertensive PDR group and nonhypertensive PDR group As shown in Table 5 , there was no significant difference in the Ang-1 concentration, Ang-2 concentration, VEGF concentration or Ang-2/Ang-1 ratio between the hypertensive PDR group and the nonhypertensive PDR group, regardless of whether the PDR group was injected. Correlations between the Ang-2/Ang-1 ratio and VEGF concentration in each group As shown in Table 6 , scatter plots were drawn to indicate the association between the Ang-2/Ang-1 ratio and the VEGF concentration in the vitreous fluid of the noninjection group, the noninjection active group, and the noninjection inactive group, and a linear, positive correlation was found between the Ang-2/Ang-1 ratio and the VEGF concentration (P < 0.05). No linear correlation was found between the Ang-2/Ang-1 ratio and the VEGF concentration in the injection, active injection, or inactive injection groups. Discussion Apoptosis, vascular endothelial permeability and vascular inflammation play important roles in diabetic retinopathy [ 32 ] . At present, many researchers are studying the pathophysiology of DR and are continuing to make efforts to seek new treatment methods. In recent years, VEGF has been identified as an important cytokine in DR, and studies have shown that the Ang/Tie-2 system may play an important role in ocular angiogenesis. Ang-1 and Ang-2 are the most well-characterized members of the angiopoietin protein family. Ang-1 regulates the stability of blood vessels by recruiting pericytes and inhibiting vascular permeability mediated by inflammatory factors, promoting receptor autophosphorylation [ 33 ] . In contrast, Ang-2 competitively blocks Ang-1/Tie-2 signaling, leading to increased inflammation, pericyte shedding, blood‒retinal barrier breakdown, and vascular instability [ 34 , 35 ] . Because the balance of Ang-1 and Ang-2 expression plays an important role in angiogenesis, inflammation, vascular remodeling, and vascular leakage, many related disease studies have focused on the imbalance between these processes to elucidate the pathogenesis of disease conditions. Elevated Ang-2 expression is associated with pathological angiogenesis during neovascularization in ischemic retinas and animal tumor models, as well as during vascular development of deep retinal capillaries. Moreover, Ang-2 expression is significantly increased in a variety of tumor models, leading to angiogenesis disorders and tissue hypoxia [ 36 ] . The concentration of Ang-2, an important pathogenic factor of DR, is increased in the vitreous and serum of PDR patients [ 37 , 38 ] . In the present study, the vitreous Ang-2 concentration was significantly greater in the PDR group than in the control group. In addition, in the present study, the concentration of Ang-2 in the vitreous of the active PDR group was greater than that in the vitreous of the inactive PDR group in both the injection group and the noninjection group, suggesting that Ang-2 may play a role in promoting pathological angiogenesis in PDR. In the present study, the concentration of Ang-1 in the vitreous was significantly greater in the PDR group than in the control group. An increase in Ang-1 expression in DR serum may be a compensatory mechanism that helps to repair cells and maintain the integrity of endothelial cells, thereby promoting the stability and maturation of new microvessels and the integrity of microvascular structures [ 39 ] . In the noninjection group, no significant difference in the Ang-1 concentration was found between the active and inactive PDR groups. The concentration of Ang-1 in the vitreous of the active PDR group was lower than that in the vitreous of the inactive PDR group. The reason for this difference is uncertain, and one possible reason is that performing intravitreal anti-VEGF injections affects Ang-1 concentrations. As VEGF is a key regulator affecting PDR, we also evaluated the expression level of VEGF in the vitreous of PDR eyes. The results of this experiment showed that the average VEGF concentration in the vitreous of the experimental group was significantly greater than that in the vitreous of the control group, and the concentration of VEGF in the vitreous of the control group was lower than that measured by ELISA. In this study, in the noninjected group, the concentration of VEGF in the vitreous of the active PDR group was greater than that in the vitreous of the inactive PDR group, indicating that neovascularization further aggravated hypoxia and promoted the production of VEGF. However, in the injection group, no significant difference in VEGF concentration was found between the active PDR group and the inactive PDR group. This may be related to the decrease in the VEGF concentration in the vitreous caused by the intravitreal injection of anti-VEGF drugs, resulting in no difference in the VEGF concentrations of the active and inactive groups. Anti-VEGF drugs, as first-line drugs for the treatment of DR and PDR, can eliminate the release of VEGF in ischemic peripheral retinal cells so that other ischemic retinopathies, such as DR and PDR, can be relieved to a certain extent, achieve therapeutic effects, and help to reduce intraoperative bleeding. VEGF levels are elevated in the plasma of hypertensive patients. The increase in plasma Ang-2 levels in hypertensive patients may represent vascular remodeling. However, there was no significant difference in Ang-1, Ang-2, VEGF expression, or the Ang-2/Ang-1 expression ratio between the hypertensive PDR group and the nonhypertensive PDR group in the present study. These results may be because a history of hypertension was not one of the factors affecting the changes in Ang-1, Ang-2, VEGF expression, or the Ang-2/Ang-1 expression ratio in the vitreous humor of PDR patients. According to previous studies, a decreased Ang-1/Ang-2 expression ratio facilitates angiogenesis, has some value in evaluating certain cancer prognoses, and is associated with tumor progression, angiogenesis, metastasis, and patient survival [ 40 ] . In acute respiratory distress syndrome [ 41 ] , an elevated Ang-2/Ang-1 expression ratio predicts severe endothelial dysfunction and vascular leakage, leading to organ dysfunction. Moreover, an increased serum Ang-2/Ang-1 ratio in sepsis patients is associated with increased disease severity and poor prognosis due to hypervascular permeability [ 42 , 43 ] . Therefore, we calculated the Ang-2/Ang-1 expression ratio, which may be a better parameter for assessing the balance of the ongoing angiogenin process. Khalaf Nervana et al. demonstrated that a decrease in Ang-1/Ang-2 expression in the serum of DR patients is negatively correlated with the severity of DR [ 44 ] . In this study, the Ang-2/Ang-1 expression ratio in the vitreous of the PDR group was greater than that in the vitreous of the control group, and the Ang-2/Ang-1 expression ratio in the active PDR group was greater than that in the inactive PDR group, suggesting that the Ang-2/Ang-1 expression ratio may be a marker of vascular injury in PDR and is more sensitive than Ang-1 or Ang-2 measurement alone. There was no significant difference in the Ang-2/Ang-1 ratio between the hypertensive and nonhypertensive PDR groups. Previous studies have confirmed that Ang-2 and VEGF expression is increased in the retina and serum of patients with PDR and that the synergistic effect of Ang-2 and VEGF promotes hypoxia-induced retinal neovascularization [ 45 ] . The significant positive correlation between the Ang-2/Ang-1 ratio and vitreous VEGF concentration in the uninjected PDR group in this study validates the synergistic effect of Ang-2 and VEGF. Therefore, reducing the Ang-2/Ang-1 ratio by decreasing Ang-2 expression levels or increasing Ang-1 expression may be a new therapeutic approach for treating PDR. Our study has certain limitations. First, the number of samples included in this study was not large, and the data may not be representative of the entire population. Second, due to the safety of the operation, the vitreous fluid of the patients in the injection group could not be obtained before and after injection for self-comparison to study the effect of anti-VEGF drug treatment on the three angiogenic factors and the Ang-2/Ang-1 ratio. Conclusions In conclusion, the present study showed that the expression levels of Ang-1, Ang-2, and VEGF in the vitreous of PDR patients were significantly greater than those in the vitreous of nondiabetic patients. The expression level of Ang-2 and the Ang-2/Ang-1 expression ratio in the vitreous of active PDR patients were significantly greater than those in the vitreous of inactive PDR patients. Moreover, the present study showed that the Ang-2/Ang-1 expression ratio was correlated with VEGF expression. These findings suggest that the Ang-2/Ang-1 expression ratio and VEGF expression are associated with angiogenic activity in PDR. Patients and methods This was a cross-sectional case‒control study. Vitreous samples were collected from 60 patients (60 eyes) with PDR and macular holes who underwent standard pars propria vitrectomy (PPV) at the Eye Center of the Second Hospital of Jilin University. The patients were divided into a PDR group (50 patients) and a control group (10 patients). This study was approved by the Ethics Committee of the Second Hospital of Jilin University and was conducted in accordance with the current version of the Declaration of Helsinki. All patients were fully informed and signed consent forms. The inclusion criteria were as follows: (1) patients were over 18 years old and (2) had type 2 diabetes mellitus. The exclusion criteria were as follows: ① PDR was combined with other eye diseases, such as central retinal vein occlusion, central retinal artery occlusion or age-related macular degeneration; ② previous vitrectomy, cataract surgery, antiglaucoma surgery or other intraocular surgery; ③ previous intravitreal drug injection or periocular injection; and ④ previous retinal laser photocoagulation therapy. The patients in the PDR group were divided into an injection group (25 eyes) and a noninjection group (25 eyes) based on whether they received an intravitreal injection of conbercept before surgery. Retinopathy was classified as active if perfusion, multibranched irises or preretinal capillaries were present. Cases were classified as inactive if the previously recorded active proliferation had completely regressed or if only nonperfused, glial vessels or fibrosis were present. Based on the above characteristics, the injection group and the noninjection group were divided into an active PDR group and an inactive PDR group, respectively. According to the history of hypertension, the injection group and the non-injection group were divided into a hypertensive PDR group and a non-hypertensive PDR group, respectively. All patients were examined by slit-lamp microscopy, slit-lamp fundus examination after mydriasis, indirect ophthalmoscopy, wide-angle photography and ocular ultrasound to confirm the diagnosis and underwent a detailed eye examination after admission. Sample collection All patients underwent standard PPV after local or general anesthesia was applied. All operations were performed by the same experienced chief physician in the Department of Ophthalmology, the Second Bethune Hospital of Jilin University. A trocar was inserted in a standard fashion for three-port PPV. Prior to any surgical manipulation, the samples were manually aspirated into sterile tubes (0.3 mL) using a vitrectomy machine with perfusion turned off while cutting at 5000 cuts/min. The samples were identified, and patient age, sex, diagnosis, eye history, and date of sample collection were recorded. The samples were centrifuged at 10,000 rpm for 10 min at 4°C to remove cells and debris, and the supernatants were dispensed into sterile 1.5 ml centrifuge tubes and stored at – 80°C. ELISAbased quantification of Ang-1, Ang-2 and VEGF expression The vitreous expression of Ang-1, Ang-2 and VEGF were measured by enzyme-linked immunosorbent assay (ELISA). Ang-1, Ang-2, and VEGF expression were determined using human Ang-1, Ang-2, and VEGF ELISA kits (DANG 10, DANG 20, DVE00, R&D Systems, Minneapolis, MN, USA) according to the manufacturer’s protocol. The OD values were read using a microplate reader. When the limit was beyond the detectable range, the maximum and minimum computable values were specified for this analysis, and unqualified data were eliminated. The results were analyzed and graphed using SPSS 26 (IBM, New York, USA). Statistical analyses SPSS 26.0 (SPSS Inc., Chicago, IL, USA) was used for the statistical analysis of the collected data. Normally distributed data are expressed as the mean ± standard deviation ( \(\stackrel{-}{X}\) ±SD), and skewed data are expressed as the median (interquartile range). Paired sample t tests or paired sample rank sum tests were used to compare the differences between the PDR group and the control group, between the injection group and the noninjection group, and between the active group and the inactive group based on whether the quantitative data were normally distributed. The chi-square test and Fisher’s test were used to compare gender, history of hypertension, injection and eyes. Pearson correlation analysis or Spearman correlation analysis was used to analyze the correlation between two variables. For all the above methods, P < 0.05 was considered to indicate statistical significance. Declarations Competing interests The authors declare no competing interests. Author Contribution Preparation of the manuscript: Xiang Ma. Conception: Xiang Ma and Yan cheng. Sample collection: Xiang Ma, Yan Cheng, Yi-chun Yu and Yu-xun Zhao. Experimental operation: Xiang Ma, Bo Jia and Yan Cheng. Data curation: Xiang Ma. Analysis of data: Xiang Ma and Bo Jia. Supervision: Li-li Nie and Yan Cheng. All authors contributed toward revisions that were critical to the intellectual content and approved the final version for publication. Acknowledgements This work was supported by the National Science Foundation for Young Scholars of China (Grant No. 81800796) and the Joint Fund for the Projects of Science and Technology Development Plan of Jilin Province. (Grant No. YDZJ202101ZYTS085). Data Availability The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. References Early Treatment D. Grading Diabetic Retinopathy from Stereoscopic Color Fundus Photographs An Extension of the Modified Airlie House Classification[J]. Ophthalmology, 2020, 127(4): S99-S119. Ling R, Ramsewak V, Taylor D, et al. Longitudinal study of a cohort of people with diabetes screened by the Exeter Diabetic Retinopathy Screening Programme[J]. Eye, 2002, 16(2): 140–145. 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Tables Table 1 Patient characteristics PDR group Control group P value Age 55.17±13.029 62.1±7.355 0.031 ＊ sex （ % ） male 30（60.0） 0（0） 0.002 ＊ female 20（40.0） 10（100） Separation of eyes （ % ） Right eye 26（52.0） 4（40） 0.512 Left eye 24（48.0） 6（60） History of diabetes mellitus （ year ）（ % ） have 50（100） 0（0） 0.000 ＊ non-have 0（0） 10（100） Course of Disease （ day ） 90（30，196.5） 75.5（26.75，409.25） 0.868 History of hypertension （ year ）（ % ） have 23（46.0） 0（0） 0.006 ＊ non-have 27（54.0） 10（100） Intravitreal injection （ % ） have 25（50.0） 0（0） 0.019 ＊ non-have 25（50.0） 10（100） Intraocular pressure before surgery 15.7838±3.73 16.5±2.64 0.573 Duration of surgery （ min) 76.1351±47.43 35±13.54 0.01 ＊ ＊ P<0.05, significant difference. Table 2 Differences in the concentrations of three cytokines and the Ang-2/Ang-1 expression ratio between the PDR group and the control group PDR group N=50 Control group N=10 P value Ang1 （ pg/ml) 37.66±45.71 2.33±14.7 0.03 ＊ Ang2 （ pg/ml) 744.87±747.80 0.14±43.45 0.000 ＊ VEGF （ pg/ml) 123.72±294.14 — 0.000 ＊ Ang2/Ang1 16.66±32.92 0.36±7.36 0.009 ＊ —Indicates that the measured value is below the minimum measured range of the ELISA box ＊ P<0.05, significant difference. Table 3 Data analysis of active versus inactive three cytokines and Ang2/Ang1 ratio in the injection group Active PDR group in the injection group N=15 Non-active PDR group in the injection group N=10 P value Ang1 （ pg/ml) 4.99±29.21 56.96±51.74 0.013 ＊ Ang2 （ pg/ml) 1226.11±950.43 475.22±308.16 0.023 ＊ VEGF （ pg/ml) 11.28±11.31 11.05±5.47 0.937 Ang2/Ang1 49.92±39.67 14.55±12.65 0.046 ＊ ＊ P<0.05, significant difference. Table 4 Data analysis of active versus inactive three cytokines and Ang2/Ang1 ratio in the non-injection group Active PDR group in the non-injection group N=10 Non-active PDR group in the non-injection group N=15 P value Ang1 （ pg/ml) 39.23±24.37 56.72±57.77 0.455 Ang2 （ pg/ml) 1099.43±597.65 337.80±188.76 0.016 ＊ VEGF （ pg/ml) 445.24±490.32 134.74±166.85 0.011 ＊ Ang2/Ang1 23.32±13.52 8.55±9.26 0.017 ＊ ＊ P<0.05, significant difference. Table 5 Analysis of the three cytokines and the Ang-2/Ang-1 ratio in the hypertensive PDR group and nonhypertensive PDR group PDR group with injection Hypertension PDR group N=15 Non-hypertension PDR group N=10 P value Ang1（pg/ml) 36.19±52.76 5.66±28.74 0.112 Ang2（pg/ml) 998.56±991.41 905.80±655.29 0.235 VEGF（pg/ml) 9.86±6.89 14.15±5.83 0.138 Ang2/Ang1 35.12±41.17 30.39±21.34 0.797 PDR group without injection Hypertension PDR group N=9 Non-hypertension PDR group N=16 P value Ang1（pg/ml) 55.47±54.81 48.16±47.80 0.743 Ang2（pg/ml) 330.40±199.85 616.82±545.75 0.279 VEGF（pg/ml) 248.18±460.07 243.53±268.60 1.00 Ang2/Ang1 11.58±15.72 11.02±12.2 0.797 Table 6 Correlations between the Ang-2/Ang-1 ratio and VEGF concentration in each group Ang2/Ang1vsVEGF Pearson Spearman P value PDR group with injection -0.247 0.28 Active PDR group in the injection group -0.321 0.535 Non-active PDR group in the injection group 0.352 0.439 PDR group without injection 0.629 0.012* Active PDR group in the non-injection group 0.938 0.002** Non-active PDR group in the non-injection group 0.789 0.001** ** At the 0.01 level (two-tailed), the correlation is significant. * At the 0.05 level (two-tailed), the correlation was significant. 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Moreover, DR has become the most common cause of blindness among the working-age population in developed countries and seriously affects the quality of life of diabetic patients. According to the International Guidelines for Clinical Diabetic Retinopathy, DR can be divided into nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR). The earliest visible clinical signs of NPDR are microhemorrhages and microaneurysms, which represent damage to retinal capillaries\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. PDR is the most serious complication of DR, and 50% of untreated PDR patients develop irreversible blindness within 5 years of diagnosis\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Multiple mechanisms contribute to vision loss in DR, including metabolic changes\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e, coagulation and hemodynamic disorders\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e, hypoxia and oxidative stress\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e, and microvascular activation due to a variety of proangiogenic cytokines\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. Accumulating evidence has revealed several angiogenic factors that may contribute to the progression of DR, such as vascular endothelial growth factor\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e, basic fibroblast growth factor\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e, insulin-like growth factor\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e, tumor necrosis factor-α\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e, interleukin-1\u0026szlig;\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e, angiopoietin\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e, hepatocyte growth factor\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e, monocyte chemoattractant protein-1\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e and platelet-derived growth factor\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e, the expression of which have been detected in the vitreous of PDR patients. These angiogenic factors lead to increased retinal vascular permeability, apoptosis, vascular inflammation, chronic retinal hypoxia, and extensive retinal ischemia, ultimately leading to retinal neovascularization. Among these cytokines, the proangiogenic effect of VEGF in PDR has been confirmed by many clinical studies, and VEGF plays a key role in the development of DR\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe discovery of VEGF and the subsequent demonstration that VEGF expression is spatially and temporally restricted to regions of vascular development show that it is the driving force for developmental angiogenesis and ischemic/hypoxic regulation of retinal vessels. In addition, there was a significant correlation between increased VEGF expression in the vitreous and the severity of DR\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. As a pathogenic factor of abnormal growth and leakage of retinal blood vessels, VEGF has been deemed a therapeutic target for DR. The treatment of retinal and choroidal vascular diseases was revolutionized in the first decade of the 21st century with the introduction of VEGF blockers, which have significantly improved the prognoses of patients with these diseases, as well as preventing or even reversing PDR and DME.\u003c/p\u003e \u003cp\u003eIn addition to VEGF and the VEGF receptor system, the Ang/Tie-2 pathway constitutes another recently identified endothelial cell-specific ligand‒receptor system that is critical not only for vascular development but also for postnatal angiogenesis. Ang-1 is a potent agonist of Tie-2. Activated Tie-2 increases endothelial cell survival, adhesion, stability and endothelial barrier function and maintains the structural integrity of mature blood vessels and stabilizes the vasculature\u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e. Thus, Ang-1 expression prevents vascular leakage and pathological growth of abnormal vessels and attenuates proinflammatory responses in endothelial cells\u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. Ang-2 is a partial agonist or antagonist of Tie-2, acting as a competitive inhibitor of Ang-1 binding and ultimately leading to vascular dysfunction\u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e. In many pathological conditions, the balance of expression of the two angiopoietins is disrupted, and Ang-2 expression is relatively increased. Ang-2 expression leads to the progression of a variety of vascular diseases through an increase in vascular permeability and a pathological increase in instability\u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e. Because of the role of Ang/Tie-2 signaling in maintaining vascular homeostasis and the upregulation of Ang-2 expression in retinal and choroidal diseases\u003csup\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e, novel therapies targeting this pathway may reduce the vascular instability associated with neovascularization. In this study, the expression of Ang-1, Ang-2 and VEGF in the vitreous of 60 patient samples (50 from PDR patients and 10 from macular hole patients) were measured by ELISA to explore the changes in and significance of changes in the Ang-2/Ang-1 expression ratio and VEGF expression in the vitreous of patients with PDR.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003ePatient characteristics\u003c/h2\u003e\n \u003cp\u003eAs shown in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, there was no significant difference in the affected eye, disease duration or preoperative intraocular pressure between the PDR group and the control group (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). There were significant differences in age, sex, history of diabetes, history of hypertension, duration of operation and whether injection was performed (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eDifferences in the concentrations of three cytokines and the Ang-2/Ang-1 expression ratio between the PDR group and the control group\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eAs shown in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, the Ang-1 concentration was 37.66\u0026thinsp;\u0026plusmn;\u0026thinsp;45.71 (pg/ml) in the PDR group and 2.33\u0026thinsp;\u0026plusmn;\u0026thinsp;14.7 (pg/ml) in the control group, which was significantly lower than that in the PDR group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The Ang-2 concentration was 744.87\u0026thinsp;\u0026plusmn;\u0026thinsp;747.80 (pg/ml) in the PDR group and 0.14\u0026thinsp;\u0026plusmn;\u0026thinsp;43.45 (pg/ml) in the control group, which was significantly lower than that in the PDR group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The VEGF level in the PDR group was 123.72\u0026thinsp;\u0026plusmn;\u0026thinsp;294.14 (pg/ml) and was lower than the minimum detection range of the ELISA in the control group, which was significantly lower than that in the PDR group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The ratio of Ang-2/Ang-1 was 16.66\u0026thinsp;\u0026plusmn;\u0026thinsp;32.92 (pg/ml) in the PDR group and 0.36\u0026thinsp;\u0026plusmn;\u0026thinsp;7.36 (pg/ml) in the control group, which was significantly lower than that in the experimental group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eAnalysis of the three cytokines and Ang-2/Ang-1 ratios in the active PDR group and the inactive PDR group\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eAs shown in Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e, in the injection group, the concentration of Ang-1 in the active PDR group was lower than that in the inactive PDR group (4.99\u0026thinsp;\u0026plusmn;\u0026thinsp;29.21 pg/ml vs. 56.96\u0026thinsp;\u0026plusmn;\u0026thinsp;51.74 pg/ml; P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), the concentration of Ang-2 was greater than that in the inactive PDR group (1226.11\u0026thinsp;\u0026plusmn;\u0026thinsp;950.43 pg/ml vs. 475.22\u0026thinsp;\u0026plusmn;\u0026thinsp;308.16 pg/ml; P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and the ratio of Ang-2/Ang-1 was greater than that in the inactive PDR group (49.92\u0026thinsp;\u0026plusmn;\u0026thinsp;39.67 pg/ml vs. 14.55\u0026thinsp;\u0026plusmn;\u0026thinsp;12.65 pg/ml; P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). There was no significant difference in the VEGF concentration between the active PDR group and the inactive PDR group (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\n \u003cp\u003eAs shown in Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e, in the noninjected group, the concentration of Ang-2 in the active PDR group was greater than that in the inactive PDR group (1099.43\u0026thinsp;\u0026plusmn;\u0026thinsp;597.65 pg/ml vs. 337.80\u0026thinsp;\u0026plusmn;\u0026thinsp;188.76 pg/ml; P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), the concentration of VEGF was greater than that in the inactive PDR group (445.24\u0026thinsp;\u0026plusmn;\u0026thinsp;490.32 pg/ml vs. 134.74\u0026thinsp;\u0026plusmn;\u0026thinsp;166.85 pg/ml; P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and the ratio of Ang-2/Ang-1 was greater than that in the inactive PDR group (23.32\u0026thinsp;\u0026plusmn;\u0026thinsp;13.52 pg/ml vs. 8.55\u0026thinsp;\u0026plusmn;\u0026thinsp;9.26 pg/ml; P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). In the noninjection group, there was no significant difference in the Ang-1 concentration between the active PDR group and the inactive PDR group (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\n \u003cdiv align=\"char\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\n \u003cdiv align=\"char\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\n \u003cdiv align=\"char\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eAnalysis of the three cytokines and the Ang-2/Ang-1 ratio in the hypertensive PDR group and nonhypertensive PDR group\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eAs shown in Table \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e, there was no significant difference in the Ang-1 concentration, Ang-2 concentration, VEGF concentration or Ang-2/Ang-1 ratio between the hypertensive PDR group and the nonhypertensive PDR group, regardless of whether the PDR group was injected.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003eCorrelations between the Ang-2/Ang-1 ratio and VEGF concentration in each group\u003c/h2\u003e\n \u003cp\u003eAs shown in Table \u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e, scatter plots were drawn to indicate the association between the Ang-2/Ang-1 ratio and the VEGF concentration in the vitreous fluid of the noninjection group, the noninjection active group, and the noninjection inactive group, and a linear, positive correlation was found between the Ang-2/Ang-1 ratio and the VEGF concentration (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). No linear correlation was found between the Ang-2/Ang-1 ratio and the VEGF concentration in the injection, active injection, or inactive injection groups.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eApoptosis, vascular endothelial permeability and vascular inflammation play important roles in diabetic retinopathy\u003csup\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e. At present, many researchers are studying the pathophysiology of DR and are continuing to make efforts to seek new treatment methods. In recent years, VEGF has been identified as an important cytokine in DR, and studies have shown that the Ang/Tie-2 system may play an important role in ocular angiogenesis. Ang-1 and Ang-2 are the most well-characterized members of the angiopoietin protein family. Ang-1 regulates the stability of blood vessels by recruiting pericytes and inhibiting vascular permeability mediated by inflammatory factors, promoting receptor autophosphorylation\u003csup\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e. In contrast, Ang-2 competitively blocks Ang-1/Tie-2 signaling, leading to increased inflammation, pericyte shedding, blood‒retinal barrier breakdown, and vascular instability\u003csup\u003e[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e. Because the balance of Ang-1 and Ang-2 expression plays an important role in angiogenesis, inflammation, vascular remodeling, and vascular leakage, many related disease studies have focused on the imbalance between these processes to elucidate the pathogenesis of disease conditions.\u003c/p\u003e \u003cp\u003eElevated Ang-2 expression is associated with pathological angiogenesis during neovascularization in ischemic retinas and animal tumor models, as well as during vascular development of deep retinal capillaries. Moreover, Ang-2 expression is significantly increased in a variety of tumor models, leading to angiogenesis disorders and tissue hypoxia\u003csup\u003e[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e. The concentration of Ang-2, an important pathogenic factor of DR, is increased in the vitreous and serum of PDR patients\u003csup\u003e[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/sup\u003e. In the present study, the vitreous Ang-2 concentration was significantly greater in the PDR group than in the control group. In addition, in the present study, the concentration of Ang-2 in the vitreous of the active PDR group was greater than that in the vitreous of the inactive PDR group in both the injection group and the noninjection group, suggesting that Ang-2 may play a role in promoting pathological angiogenesis in PDR. In the present study, the concentration of Ang-1 in the vitreous was significantly greater in the PDR group than in the control group. An increase in Ang-1 expression in DR serum may be a compensatory mechanism that helps to repair cells and maintain the integrity of endothelial cells, thereby promoting the stability and maturation of new microvessels and the integrity of microvascular structures\u003csup\u003e[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn the noninjection group, no significant difference in the Ang-1 concentration was found between the active and inactive PDR groups. The concentration of Ang-1 in the vitreous of the active PDR group was lower than that in the vitreous of the inactive PDR group. The reason for this difference is uncertain, and one possible reason is that performing intravitreal anti-VEGF injections affects Ang-1 concentrations.\u003c/p\u003e \u003cp\u003eAs VEGF is a key regulator affecting PDR, we also evaluated the expression level of VEGF in the vitreous of PDR eyes. The results of this experiment showed that the average VEGF concentration in the vitreous of the experimental group was significantly greater than that in the vitreous of the control group, and the concentration of VEGF in the vitreous of the control group was lower than that measured by ELISA. In this study, in the noninjected group, the concentration of VEGF in the vitreous of the active PDR group was greater than that in the vitreous of the inactive PDR group, indicating that neovascularization further aggravated hypoxia and promoted the production of VEGF. However, in the injection group, no significant difference in VEGF concentration was found between the active PDR group and the inactive PDR group. This may be related to the decrease in the VEGF concentration in the vitreous caused by the intravitreal injection of anti-VEGF drugs, resulting in no difference in the VEGF concentrations of the active and inactive groups. Anti-VEGF drugs, as first-line drugs for the treatment of DR and PDR, can eliminate the release of VEGF in ischemic peripheral retinal cells so that other ischemic retinopathies, such as DR and PDR, can be relieved to a certain extent, achieve therapeutic effects, and help to reduce intraoperative bleeding.\u003c/p\u003e \u003cp\u003eVEGF levels are elevated in the plasma of hypertensive patients. The increase in plasma Ang-2 levels in hypertensive patients may represent vascular remodeling. However, there was no significant difference in Ang-1, Ang-2, VEGF expression, or the Ang-2/Ang-1 expression ratio between the hypertensive PDR group and the nonhypertensive PDR group in the present study. These results may be because a history of hypertension was not one of the factors affecting the changes in Ang-1, Ang-2, VEGF expression, or the Ang-2/Ang-1 expression ratio in the vitreous humor of PDR patients.\u003c/p\u003e \u003cp\u003eAccording to previous studies, a decreased Ang-1/Ang-2 expression ratio facilitates angiogenesis, has some value in evaluating certain cancer prognoses, and is associated with tumor progression, angiogenesis, metastasis, and patient survival\u003csup\u003e[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/sup\u003e. In acute respiratory distress syndrome\u003csup\u003e[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]\u003c/sup\u003e, an elevated Ang-2/Ang-1 expression ratio predicts severe endothelial dysfunction and vascular leakage, leading to organ dysfunction. Moreover, an increased serum Ang-2/Ang-1 ratio in sepsis patients is associated with increased disease severity and poor prognosis due to hypervascular permeability\u003csup\u003e[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]\u003c/sup\u003e. Therefore, we calculated the Ang-2/Ang-1 expression ratio, which may be a better parameter for assessing the balance of the ongoing angiogenin process. Khalaf Nervana et al. demonstrated that a decrease in Ang-1/Ang-2 expression in the serum of DR patients is negatively correlated with the severity of DR\u003csup\u003e[\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]\u003c/sup\u003e. In this study, the Ang-2/Ang-1 expression ratio in the vitreous of the PDR group was greater than that in the vitreous of the control group, and the Ang-2/Ang-1 expression ratio in the active PDR group was greater than that in the inactive PDR group, suggesting that the Ang-2/Ang-1 expression ratio may be a marker of vascular injury in PDR and is more sensitive than Ang-1 or Ang-2 measurement alone. There was no significant difference in the Ang-2/Ang-1 ratio between the hypertensive and nonhypertensive PDR groups. Previous studies have confirmed that Ang-2 and VEGF expression is increased in the retina and serum of patients with PDR and that the synergistic effect of Ang-2 and VEGF promotes hypoxia-induced retinal neovascularization\u003csup\u003e[\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]\u003c/sup\u003e. The significant positive correlation between the Ang-2/Ang-1 ratio and vitreous VEGF concentration in the uninjected PDR group in this study validates the synergistic effect of Ang-2 and VEGF. Therefore, reducing the Ang-2/Ang-1 ratio by decreasing Ang-2 expression levels or increasing Ang-1 expression may be a new therapeutic approach for treating PDR.\u003c/p\u003e \u003cp\u003eOur study has certain limitations. First, the number of samples included in this study was not large, and the data may not be representative of the entire population. Second, due to the safety of the operation, the vitreous fluid of the patients in the injection group could not be obtained before and after injection for self-comparison to study the effect of anti-VEGF drug treatment on the three angiogenic factors and the Ang-2/Ang-1 ratio.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, the present study showed that the expression levels of Ang-1, Ang-2, and VEGF in the vitreous of PDR patients were significantly greater than those in the vitreous of nondiabetic patients. The expression level of Ang-2 and the Ang-2/Ang-1 expression ratio in the vitreous of active PDR patients were significantly greater than those in the vitreous of inactive PDR patients. Moreover, the present study showed that the Ang-2/Ang-1 expression ratio was correlated with VEGF expression. These findings suggest that the Ang-2/Ang-1 expression ratio and VEGF expression are associated with angiogenic activity in PDR.\u003c/p\u003e"},{"header":"Patients and methods","content":"\u003cp\u003eThis was a cross-sectional case‒control study. Vitreous samples were collected from 60 patients (60 eyes) with PDR and macular holes who underwent standard pars propria vitrectomy (PPV) at the Eye Center of the Second Hospital of Jilin University. The patients were divided into a PDR group (50 patients) and a control group (10 patients). This study was approved by the Ethics Committee of the Second Hospital of Jilin University and was conducted in accordance with the current version of the Declaration of Helsinki. All patients were fully informed and signed consent forms.\u003c/p\u003e \u003cp\u003eThe inclusion criteria were as follows: (1) patients were over 18 years old and (2) had type 2 diabetes mellitus. The exclusion criteria were as follows: ① PDR was combined with other eye diseases, such as central retinal vein occlusion, central retinal artery occlusion or age-related macular degeneration; ② previous vitrectomy, cataract surgery, antiglaucoma surgery or other intraocular surgery; ③ previous intravitreal drug injection or periocular injection; and ④ previous retinal laser photocoagulation therapy.\u003c/p\u003e \u003cp\u003eThe patients in the PDR group were divided into an injection group (25 eyes) and a noninjection group (25 eyes) based on whether they received an intravitreal injection of conbercept before surgery. Retinopathy was classified as active if perfusion, multibranched irises or preretinal capillaries were present. Cases were classified as inactive if the previously recorded active proliferation had completely regressed or if only nonperfused, glial vessels or fibrosis were present. Based on the above characteristics, the injection group and the noninjection group were divided into an active PDR group and an inactive PDR group, respectively. According to the history of hypertension, the injection group and the non-injection group were divided into a hypertensive PDR group and a non-hypertensive PDR group, respectively. All patients were examined by slit-lamp microscopy, slit-lamp fundus examination after mydriasis, indirect ophthalmoscopy, wide-angle photography and ocular ultrasound to confirm the diagnosis and underwent a detailed eye examination after admission.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eSample collection\u003c/h2\u003e \u003cp\u003eAll patients underwent standard PPV after local or general anesthesia was applied. All operations were performed by the same experienced chief physician in the Department of Ophthalmology, the Second Bethune Hospital of Jilin University. A trocar was inserted in a standard fashion for three-port PPV. Prior to any surgical manipulation, the samples were manually aspirated into sterile tubes (0.3 mL) using a vitrectomy machine with perfusion turned off while cutting at 5000 cuts/min. The samples were identified, and patient age, sex, diagnosis, eye history, and date of sample collection were recorded. The samples were centrifuged at 10,000 rpm for 10 min at 4\u0026deg;C to remove cells and debris, and the supernatants were dispensed into sterile 1.5 ml centrifuge tubes and stored at \u0026ndash; 80\u0026deg;C.\u003c/p\u003e \u003cp\u003eELISAbased quantification of Ang-1, Ang-2 and VEGF expression\u003c/p\u003e \u003cp\u003eThe vitreous expression of Ang-1, Ang-2 and VEGF were measured by enzyme-linked immunosorbent assay (ELISA). Ang-1, Ang-2, and VEGF expression were determined using human Ang-1, Ang-2, and VEGF ELISA kits (DANG 10, DANG 20, DVE00, R\u0026amp;D Systems, Minneapolis, MN, USA) according to the manufacturer\u0026rsquo;s protocol. The OD values were read using a microplate reader. When the limit was beyond the detectable range, the maximum and minimum computable values were specified for this analysis, and unqualified data were eliminated. The results were analyzed and graphed using SPSS 26 (IBM, New York, USA).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eSPSS 26.0 (SPSS Inc., Chicago, IL, USA) was used for the statistical analysis of the collected data. Normally distributed data are expressed as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\stackrel{-}{X}\\)\u003c/span\u003e\u003c/span\u003e\u0026plusmn;SD), and skewed data are expressed as the median (interquartile range). Paired sample t tests or paired sample rank sum tests were used to compare the differences between the PDR group and the control group, between the injection group and the noninjection group, and between the active group and the inactive group based on whether the quantitative data were normally distributed. The chi-square test and Fisher\u0026rsquo;s test were used to compare gender, history of hypertension, injection and eyes. Pearson correlation analysis or Spearman correlation analysis was used to analyze the correlation between two variables. For all the above methods, \u003cem\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/em\u003e was considered to indicate statistical significance.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003ePreparation of the manuscript: Xiang Ma. Conception: Xiang Ma and Yan cheng. Sample collection: Xiang Ma, Yan Cheng, Yi-chun Yu and Yu-xun Zhao. Experimental operation: Xiang Ma, Bo Jia and Yan Cheng. Data curation: Xiang Ma. Analysis of data: Xiang Ma and Bo Jia. Supervision: Li-li Nie and Yan Cheng. All authors contributed toward revisions that were critical to the intellectual content and approved the final version for publication.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eThis work was supported by the National Science Foundation for Young Scholars of China (Grant No. 81800796) and the Joint Fund for the Projects of Science and Technology Development Plan of Jilin Province. (Grant No. YDZJ202101ZYTS085).\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eEarly Treatment D. Grading Diabetic Retinopathy from Stereoscopic Color Fundus Photographs An Extension of the Modified Airlie House Classification[J]. 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Angiopoietin 2 expression in the retina: Upregulation during physiologic and pathologic neovascularization[J]. Journal of Cellular Physiology, 2000, 184(3): 275\u0026ndash;284.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHammes H P, Lin J H, Wagner P, et al. Angiopoietin-2 causes pericyte dropout in the normal retina - Evidence for involvement in diabetic retinopathy[J]. Diabetes, 2004, 53(4): 1104\u0026ndash;1110.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGale N W, Thurston G, Hackett S F, et al. Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by angiopoietin-1[J]. Developmental Cell, 2002, 3(3): 411\u0026ndash;423.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePfister F, Wang Y, Schreiter K, et al. Retinal overexpression of angiopoietin-2 mimics diabetic retinopathy and enhances vascular damages in hyperglycemia[J]. Acta Diabetologica, 2010, 47(1): 59\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen C, Chen X, Huang H, et al. Elevated plasma and vitreous levels of leucine-rich-α2-glycoprotein are associated with diabetic retinopathy progression[J]. Acta Ophthalmologica, 2019, 97(3): 260\u0026ndash;264.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLip P L, Chatterjee S, Caine G J, et al. Plasma vascular endothelial growth factor, angiopoietin-2, and soluble angiopoietin receptor tie-2 in diabetic retinopathy: effects of laser photocoagulation and angiotensin receptor blockade[J]. British Journal of Ophthalmology, 2004, 88(12): 1543\u0026ndash;1546.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaharinen P, Eklund L, Pulkki K, et al. VEGF and angiopoietin signaling in tumor angiogenesis and metastasis[J]. Trends in Molecular Medicine, 2011, 17(7): 347\u0026ndash;362.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWada T, Jesmin S, Gando S, et al. The role of angiogenic factors and their soluble receptors in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) associated with critical illness[J]. Journal of Inflammation-London, 2013, 10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZiegler T, Horstkotte J, Schwab C, et al. Angiopoietin 2 mediates microvascular and hemodynamic alterations in sepsis[J]. Journal of Clinical Investigation, 2013, 123(8): 3436\u0026ndash;3445.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOrfanos S E, Kotanidou A, Glynos C, et al. Angiopoietin-2 is increased in severe sepsis: Correlation with inflammatory mediators[J]. Critical Care Medicine, 2007, 35(1): 199\u0026ndash;206.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhalaf N, Helmy H, Labib H, et al. Role of Angiopoietins and Tie-2 in Diabetic Retinopathy[J]. Electronic physician, 2017, 9(8): 5031\u0026ndash;5035.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWilkinson-Berka J L, Rizkalla B, Moravski C, et al. Retinal angiogenesis is mediated by an interaction between the angiotensin Type 2 receptor, VEGF and angiopoietin[J]. Diabetologia, 2003, 46: A67-A67.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 Patient characteristics\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"551\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.415607985480943%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.337568058076226%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.049001814882033%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePDR group\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.76769509981851%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eControl group\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.430127041742287%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.415607985480943%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.337568058076226%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.049001814882033%\" valign=\"top\"\u003e\n \u003cp\u003e55.17\u0026plusmn;13.029\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.76769509981851%\" valign=\"top\"\u003e\n \u003cp\u003e62.1\u0026plusmn;7.355\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.430127041742287%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.031\u003c/strong\u003e＊\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.415607985480943%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003esex\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.337568058076226%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.049001814882033%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.76769509981851%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.430127041742287%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.415607985480943%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.337568058076226%\" valign=\"top\"\u003e\n \u003cp\u003emale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.049001814882033%\" valign=\"top\"\u003e\n \u003cp\u003e30（60.0）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.76769509981851%\" valign=\"top\"\u003e\n \u003cp\u003e0（0）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.430127041742287%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.002\u003c/strong\u003e＊\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.415607985480943%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.337568058076226%\" valign=\"top\"\u003e\n \u003cp\u003efemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.049001814882033%\" valign=\"top\"\u003e\n \u003cp\u003e20（40.0）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.76769509981851%\" valign=\"top\"\u003e\n \u003cp\u003e10（100）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.430127041742287%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.415607985480943%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSeparation of eyes\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.337568058076226%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.049001814882033%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.76769509981851%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.430127041742287%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.415607985480943%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.337568058076226%\" valign=\"top\"\u003e\n \u003cp\u003eRight eye\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.049001814882033%\" valign=\"top\"\u003e\n \u003cp\u003e26（52.0）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.76769509981851%\" valign=\"top\"\u003e\n \u003cp\u003e4（40）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.430127041742287%\" valign=\"top\"\u003e\n \u003cp\u003e0.512\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.415607985480943%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.337568058076226%\" valign=\"top\"\u003e\n \u003cp\u003eLeft eye\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.049001814882033%\" valign=\"top\"\u003e\n \u003cp\u003e24（48.0）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.76769509981851%\" valign=\"top\"\u003e\n \u003cp\u003e6（60）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.430127041742287%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.415607985480943%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eHistory of diabetes mellitus\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003eyear\u003c/strong\u003e\u003cstrong\u003e）（\u003c/strong\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.337568058076226%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.049001814882033%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.76769509981851%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.430127041742287%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.415607985480943%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.337568058076226%\" valign=\"top\"\u003e\n \u003cp\u003ehave\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.049001814882033%\" valign=\"top\"\u003e\n \u003cp\u003e50（100）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.76769509981851%\" valign=\"top\"\u003e\n \u003cp\u003e0（0）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.430127041742287%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.000\u003c/strong\u003e＊\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.415607985480943%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.337568058076226%\" valign=\"top\"\u003e\n \u003cp\u003enon-have\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.049001814882033%\" valign=\"top\"\u003e\n \u003cp\u003e0（0）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.76769509981851%\" valign=\"top\"\u003e\n \u003cp\u003e10（100）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.430127041742287%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.415607985480943%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCourse of Disease\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003eday\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.337568058076226%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.049001814882033%\" valign=\"top\"\u003e\n \u003cp\u003e90（30，196.5）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.76769509981851%\" valign=\"top\"\u003e\n \u003cp\u003e75.5（26.75，409.25）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.430127041742287%\" valign=\"top\"\u003e\n \u003cp\u003e0.868\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.415607985480943%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eHistory of hypertension\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003eyear\u003c/strong\u003e\u003cstrong\u003e）（\u003c/strong\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.337568058076226%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.049001814882033%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.76769509981851%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.430127041742287%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.415607985480943%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.337568058076226%\" valign=\"top\"\u003e\n \u003cp\u003ehave\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.049001814882033%\" valign=\"top\"\u003e\n \u003cp\u003e23（46.0）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.76769509981851%\" valign=\"top\"\u003e\n \u003cp\u003e0（0）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.430127041742287%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.006\u003c/strong\u003e＊\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.415607985480943%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.337568058076226%\" valign=\"top\"\u003e\n \u003cp\u003enon-have\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.049001814882033%\" valign=\"top\"\u003e\n \u003cp\u003e27（54.0）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.76769509981851%\" valign=\"top\"\u003e\n \u003cp\u003e10（100）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.430127041742287%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.415607985480943%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eIntravitreal injection\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.337568058076226%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.049001814882033%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.76769509981851%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.430127041742287%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.415607985480943%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.337568058076226%\" valign=\"top\"\u003e\n \u003cp\u003ehave\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.049001814882033%\" valign=\"top\"\u003e\n \u003cp\u003e25（50.0）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.76769509981851%\" valign=\"top\"\u003e\n \u003cp\u003e0（0）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.430127041742287%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.019\u003c/strong\u003e＊\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.415607985480943%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.337568058076226%\" valign=\"top\"\u003e\n \u003cp\u003enon-have\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.049001814882033%\" valign=\"top\"\u003e\n \u003cp\u003e25（50.0）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.76769509981851%\" valign=\"top\"\u003e\n \u003cp\u003e10（100）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.430127041742287%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.415607985480943%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eIntraocular pressure before surgery\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.337568058076226%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.049001814882033%\" valign=\"top\"\u003e\n \u003cp\u003e15.7838\u0026plusmn;3.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.76769509981851%\" valign=\"top\"\u003e\n \u003cp\u003e16.5\u0026plusmn;2.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.430127041742287%\" valign=\"top\"\u003e\n \u003cp\u003e0.573\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.415607985480943%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDuration of surgery\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003emin)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.337568058076226%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.049001814882033%\" valign=\"top\"\u003e\n \u003cp\u003e76.1351\u0026plusmn;47.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.76769509981851%\" valign=\"top\"\u003e\n \u003cp\u003e35\u0026plusmn;13.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.430127041742287%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.01\u003c/strong\u003e＊\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e＊\u003cem\u003eP\u0026lt;0.05,\u0026nbsp;\u003c/em\u003esignificant difference.\u003c/p\u003e\n\u003cp\u003eTable 2 \u0026nbsp;Differences in the concentrations of three cytokines and the Ang-2/Ang-1 expression ratio between the PDR group and the control group\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.428571428571427%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.551020408163264%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePDR group\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN=50\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.510204081632654%\"\u003e\n \u003cp\u003e\u003cstrong\u003eControl group\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN=10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.510204081632654%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.428571428571427%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAng1\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003epg/ml)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.551020408163264%\"\u003e\n \u003cp\u003e37.66\u0026plusmn;45.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.510204081632654%\"\u003e\n \u003cp\u003e2.33\u0026plusmn;14.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.510204081632654%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.03\u003c/strong\u003e＊\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.428571428571427%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAng2\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003epg/ml)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.551020408163264%\"\u003e\n \u003cp\u003e744.87\u0026plusmn;747.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.510204081632654%\"\u003e\n \u003cp\u003e0.14\u0026plusmn;43.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.510204081632654%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.000\u003c/strong\u003e＊\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.428571428571427%\"\u003e\n \u003cp\u003e\u003cstrong\u003eVEGF\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003epg/ml)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.551020408163264%\"\u003e\n \u003cp\u003e123.72\u0026plusmn;294.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.510204081632654%\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.510204081632654%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.000\u003c/strong\u003e＊\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.428571428571427%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAng2/Ang1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.551020408163264%\"\u003e\n \u003cp\u003e16.66\u0026plusmn;32.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.510204081632654%\"\u003e\n \u003cp\u003e0.36\u0026plusmn;7.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.510204081632654%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.009\u003c/strong\u003e＊\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026mdash;Indicates that the measured value is below the minimum measured range of the ELISA box\u003c/p\u003e\n\u003cp\u003e＊\u003cem\u003eP\u0026lt;0.05,\u0026nbsp;\u003c/em\u003esignificant difference.\u003c/p\u003e\n\u003cp\u003eTable 3 \u0026nbsp;Data analysis of active versus inactive three cytokines and Ang2/Ang1 ratio in the injection group\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"102%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.428571428571427%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eActive PDR group in the injection group\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN=15\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNon-active PDR group in the injection group\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN=10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.510204081632654%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.428571428571427%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAng1\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003epg/ml)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" valign=\"top\"\u003e\n \u003cp\u003e4.99\u0026plusmn;29.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" valign=\"top\"\u003e\n \u003cp\u003e56.96\u0026plusmn;51.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.510204081632654%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.013\u003c/strong\u003e＊\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.428571428571427%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAng2\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003epg/ml)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" valign=\"top\"\u003e\n \u003cp\u003e1226.11\u0026plusmn;950.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" valign=\"top\"\u003e\n \u003cp\u003e475.22\u0026plusmn;308.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.510204081632654%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.023\u003c/strong\u003e＊\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.428571428571427%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eVEGF\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003epg/ml)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" valign=\"top\"\u003e\n \u003cp\u003e11.28\u0026plusmn;11.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" valign=\"top\"\u003e\n \u003cp\u003e11.05\u0026plusmn;5.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.510204081632654%\" valign=\"top\"\u003e\n \u003cp\u003e0.937\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.428571428571427%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAng2/Ang1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" valign=\"top\"\u003e\n \u003cp\u003e49.92\u0026plusmn;39.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" valign=\"top\"\u003e\n \u003cp\u003e14.55\u0026plusmn;12.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.510204081632654%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.046\u003c/strong\u003e＊\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e＊\u003cem\u003eP\u0026lt;0.05,\u0026nbsp;\u003c/em\u003esignificant difference.\u003c/p\u003e\n\u003cp\u003eTable 4 \u0026nbsp;Data analysis of active versus inactive three cytokines and Ang2/Ang1 ratio in the non-injection group\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"144%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.428571428571427%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.591836734693878%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eActive PDR group in the non-injection group\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN=10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.816326530612244%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNon-active PDR group in the non-injection group\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN=15\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.16326530612245%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003evalue\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.428571428571427%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAng1\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003epg/ml)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.591836734693878%\" valign=\"top\"\u003e\n \u003cp\u003e39.23\u0026plusmn;24.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.816326530612244%\" valign=\"top\"\u003e\n \u003cp\u003e56.72\u0026plusmn;57.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.16326530612245%\" valign=\"top\"\u003e\n \u003cp\u003e0.455\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.428571428571427%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAng2\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003epg/ml)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.591836734693878%\" valign=\"top\"\u003e\n \u003cp\u003e1099.43\u0026plusmn;597.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.816326530612244%\" valign=\"top\"\u003e\n \u003cp\u003e337.80\u0026plusmn;188.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.16326530612245%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.016\u003c/strong\u003e＊\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.428571428571427%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eVEGF\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003epg/ml)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.591836734693878%\" valign=\"top\"\u003e\n \u003cp\u003e445.24\u0026plusmn;490.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.816326530612244%\" valign=\"top\"\u003e\n \u003cp\u003e134.74\u0026plusmn;166.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.16326530612245%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.011\u003c/strong\u003e＊\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.428571428571427%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAng2/Ang1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.591836734693878%\" valign=\"top\"\u003e\n \u003cp\u003e23.32\u0026plusmn;13.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.816326530612244%\" valign=\"top\"\u003e\n \u003cp\u003e8.55\u0026plusmn;9.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.16326530612245%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.017\u003c/strong\u003e＊\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e＊\u003cem\u003eP\u0026lt;0.05,\u0026nbsp;\u003c/em\u003esignificant difference.\u003c/p\u003e\n\u003cp\u003eTable 5 \u0026nbsp;Analysis of the three cytokines and the Ang-2/Ang-1 ratio in the hypertensive PDR group and nonhypertensive PDR group\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"98%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003ePDR group with injection\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.448979591836736%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" valign=\"top\"\u003e\n \u003cp\u003eHypertension PDR group\u003c/p\u003e\n \u003cp\u003eN=15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" valign=\"top\"\u003e\n \u003cp\u003eNon-hypertension PDR group\u003c/p\u003e\n \u003cp\u003eN=10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.448979591836736%\" valign=\"top\"\u003e\n \u003cp\u003eAng1（pg/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" valign=\"top\"\u003e\n \u003cp\u003e36.19\u0026plusmn;52.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" valign=\"top\"\u003e\n \u003cp\u003e5.66\u0026plusmn;28.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003e0.112\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.448979591836736%\" valign=\"top\"\u003e\n \u003cp\u003eAng2（pg/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" valign=\"top\"\u003e\n \u003cp\u003e998.56\u0026plusmn;991.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" valign=\"top\"\u003e\n \u003cp\u003e905.80\u0026plusmn;655.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003e0.235\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.448979591836736%\" valign=\"top\"\u003e\n \u003cp\u003eVEGF（pg/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" valign=\"top\"\u003e\n \u003cp\u003e9.86\u0026plusmn;6.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" valign=\"top\"\u003e\n \u003cp\u003e14.15\u0026plusmn;5.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003e0.138\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.448979591836736%\" valign=\"top\"\u003e\n \u003cp\u003eAng2/Ang1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" valign=\"top\"\u003e\n \u003cp\u003e35.12\u0026plusmn;41.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" valign=\"top\"\u003e\n \u003cp\u003e30.39\u0026plusmn;21.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003e0.797\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"568\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003ePDR group without injection\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.92768959435626%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.631393298059965%\" valign=\"top\"\u003e\n \u003cp\u003eHypertension PDR group\u003c/p\u003e\n \u003cp\u003eN=9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.278659611992946%\" valign=\"top\"\u003e\n \u003cp\u003eNon-hypertension PDR group\u003c/p\u003e\n \u003cp\u003eN=16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.16225749559083%\" valign=\"top\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.92768959435626%\" valign=\"top\"\u003e\n \u003cp\u003eAng1（pg/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.631393298059965%\" valign=\"top\"\u003e\n \u003cp\u003e55.47\u0026plusmn;54.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.278659611992946%\" valign=\"top\"\u003e\n \u003cp\u003e48.16\u0026plusmn;47.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.16225749559083%\" valign=\"top\"\u003e\n \u003cp\u003e0.743\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.92768959435626%\" valign=\"top\"\u003e\n \u003cp\u003eAng2（pg/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.631393298059965%\" valign=\"top\"\u003e\n \u003cp\u003e330.40\u0026plusmn;199.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.278659611992946%\" valign=\"top\"\u003e\n \u003cp\u003e616.82\u0026plusmn;545.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.16225749559083%\" valign=\"top\"\u003e\n \u003cp\u003e0.279\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.92768959435626%\" valign=\"top\"\u003e\n \u003cp\u003eVEGF（pg/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.631393298059965%\" valign=\"top\"\u003e\n \u003cp\u003e248.18\u0026plusmn;460.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.278659611992946%\" valign=\"top\"\u003e\n \u003cp\u003e243.53\u0026plusmn;268.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.16225749559083%\" valign=\"top\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.92768959435626%\" valign=\"top\"\u003e\n \u003cp\u003eAng2/Ang1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.631393298059965%\" valign=\"top\"\u003e\n \u003cp\u003e11.58\u0026plusmn;15.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.278659611992946%\" valign=\"top\"\u003e\n \u003cp\u003e11.02\u0026plusmn;12.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.16225749559083%\" valign=\"top\"\u003e\n \u003cp\u003e0.797\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eTable 6 \u0026nbsp;Correlations between the Ang-2/Ang-1 ratio and VEGF concentration in each group\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"528\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.67296786389414%\" style=\"width: 36.8522%;\"\u003e\n \u003cp\u003eAng2/Ang1vsVEGF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.117202268431%\" style=\"width: 21.881%;\"\u003e\n \u003cp\u003ePearson\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.251417769376182%\" style=\"width: 23.2246%;\"\u003e\n \u003cp\u003eSpearman\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.958412098298677%\" style=\"width: 18.0422%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.67296786389414%\" style=\"width: 36.8522%;\"\u003e\n \u003cp\u003ePDR group with injection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.117202268431%\" style=\"width: 21.881%;\"\u003e\n \u003cp\u003e-0.247\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.251417769376182%\" style=\"width: 23.2246%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.958412098298677%\" style=\"width: 18.0422%;\"\u003e\n \u003cp\u003e0.28\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.67296786389414%\" style=\"width: 36.8522%;\"\u003e\n \u003cp\u003eActive PDR group in the injection group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.117202268431%\" style=\"width: 21.881%;\"\u003e\n \u003cp\u003e-0.321\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.251417769376182%\" style=\"width: 23.2246%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.958412098298677%\" style=\"width: 18.0422%;\"\u003e\n \u003cp\u003e0.535\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.67296786389414%\" style=\"width: 36.8522%;\"\u003e\n \u003cp\u003eNon-active PDR group in the injection group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.117202268431%\" style=\"width: 21.881%;\"\u003e\n \u003cp\u003e0.352\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.251417769376182%\" style=\"width: 23.2246%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.958412098298677%\" style=\"width: 18.0422%;\"\u003e\n \u003cp\u003e0.439\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.67296786389414%\" style=\"width: 36.8522%;\"\u003e\n \u003cp\u003ePDR group without injection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.117202268431%\" style=\"width: 21.881%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.251417769376182%\" style=\"width: 23.2246%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.629\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.958412098298677%\" style=\"width: 18.0422%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.012*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.67296786389414%\" style=\"width: 36.8522%;\"\u003e\n \u003cp\u003eActive PDR group in the non-injection group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.117202268431%\" style=\"width: 21.881%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.938\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.251417769376182%\" style=\"width: 23.2246%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.958412098298677%\" style=\"width: 18.0422%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.002**\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.67296786389414%\" style=\"width: 36.8522%;\"\u003e\n \u003cp\u003eNon-active PDR group in the non-injection group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.117202268431%\" style=\"width: 21.881%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.251417769376182%\" style=\"width: 23.2246%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.789\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.958412098298677%\" style=\"width: 18.0422%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001**\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e** At the 0.01 level (two-tailed), the correlation is significant.\u003c/p\u003e\n\u003cp\u003e* At the 0.05 level (two-tailed), the correlation was significant.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"angiopoietin-1, angiopoietin-2, vascular endothelial growth factor, proliferative diabetic retinopathy, angiopoietin-2/angiopoietin-1","lastPublishedDoi":"10.21203/rs.3.rs-4238976/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4238976/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eTo explore the significance of the Ang-2/Ang-1 ratio and VEGF expression in the vitreous of PDR patients.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA total of 50 PDR patients were enrolled in this study, including 25 who received intravitreal conbercept injection and 25 who did not. The control group consisted of 10 patients with macular holes. Vitreous samples were collected after vitrectomy for determination of Ang-1, Ang-2 and VEGF expression levels by enzyme-linked immunosorbent assay.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe vitreous expression of Ang-1, Ang-2, and VEGF and the Ang-2/Ang-1 expression ratio were significantly greater in the PDR group than in the control group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The expression of Ang-2 and the Ang-2/Ang-1 expression ratio in the vitreous of the active PDR group were significantly greater than those of the inactive PDR group administered injection and the PDR group without injection. There was a significant positive correlation between the Ang-2/Ang-1 expression ratio and the vitreous expression of VEGF in the PDR group without injection (correlation coefficient: 0.843, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThe increased Ang-2/Ang-1 expression in the vitreous of PDR patients suggest that Ang-2/Ang-1 and VEGF expression are associated with angiogenic activity in PDR.\u003c/p\u003e","manuscriptTitle":"Expression and significance of Ang-2/Ang-1 in the vitreous of patients with proliferative diabetic retinopathy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-19 12:05:01","doi":"10.21203/rs.3.rs-4238976/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a7573570-e565-4364-bbd3-49e2d3603ee0","owner":[],"postedDate":"April 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":30813081,"name":"Health sciences/Diseases"},{"id":30813082,"name":"Health sciences/Medical research"},{"id":30813083,"name":"Health sciences/Molecular medicine"},{"id":30813084,"name":"Health sciences/Pathogenesis"},{"id":30813085,"name":"Health sciences/Risk factors"}],"tags":[],"updatedAt":"2024-04-29T14:21:32+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-19 12:05:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4238976","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4238976","identity":"rs-4238976","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}