{"paper_id":"b37cb9ee-320d-4aef-9bdc-fd387369ab43","body_text":"J of IMAB. 2024 Jan-Mar;30(1) https://www.journal-imab-bg.org 5323\nReview article\nAN INSIGHT INTO ENDOMETRIOSIS: ROLE AND\nINFLUENCE OF THE PROCESS OF ANGIOGEN-\nESIS\nNikolai Lazarov, Faisal Saghir,\nDepartment of Obstetrics and Gynecology, Medical Faculty, Trakia University,\nStara Zagora, Bulgaria.\nJournal of IMAB . 2024 Jan-Mar;30(1)Journal of IMAB\nISSN: 1312-773X\nhttps://www.journal-imab-bg.org\nABSTRACT\nIntroduction: Endometriosis is one of the most com-\nmon gynaecological disorders present in females. Accord-\ning to the implantation of ectopic endometrial tissue out-\nside of the uterine cavity, angiogenesis is an essential pre-\nrequisite for the progression of the disease.\nThe purpose  is to provide insight and a better un-\nderstanding of the role that angiogenetic factors play\nwithin endometriosis and how this can translate into more\neffective diagnostic and therapeutic approaches taken by\nmedical specialists when treating this disease.\nMaterials and methods: We conducted a review of\nthe available scientific literature on PubMed, Google\nScholar and Science Direct, which included randomized\ncontrolled trials, observational studies, prospective control-\nled studies and case reports.\nResults and Discussion: Our review of the scientific\nliterature showed that the role of angiogenesis upon the\ndevelopment of endometrial ectopic tissue is very signifi-\ncant, and a positive relationship is established with an in-\ncrease in neo-angiogenesis and a quicker rate of develop-\nment of ectopic endometrial tissue. We also found data in-\ndicating that there are a multitude of angiogenetic and anti-\nangiogenetic factors functioning in a homeostatic manner\nto provide an optimal environment for the endometrial tis-\nsue to proliferate and for translocation for the implanta-\ntion of the ectopic tissue within different locations both\nwithin the uterine cavity and distant anatomical locations\nand regions located outside of the uterine cavity.\nConclusion: Recently, the research surrounding the\nprocess of angiogenesis is positive and positive correla-\ntions have been established between the role of angiogen-\nesis and the extent to which the ectopic endometrial tissue\nproliferates.\nKeywords: endometriosis, infertility, polymorphism,\nincidence, morphogenesis,\nINTRODUCTION\nEndometriosis is an oestrogen-dependent inflamma-\ntory disease that is characterized by the presence of endome-\ntrial glands and stroma outside the realms of the uterus. It\ncan lead to chronic inflammatory reactions that may result\nin the formation of scar tissue, such as adhesions and/or\nfibrosis, confined within the pelvis. [1] Clinically, there are\ntypes characterized by way of lesion type, and these in-\nclude; Superficial endometriosis, which is found mainly in\nthe pelvic peritoneum; cystic ovarian endometriosis, which\nis found in the ovaries, deep endometriosis, which is found\nin the recto-vaginal septum, bladder, bowel and in some\nrare cases it can also be found outside of the pelvis. En-\ndometriosis lesions are primarily located on the pelvic peri-\ntoneum and ovaries but can slowly disseminate via\nhematogenic and lymphatic routes to the pericardium,\npleura of the lung, lung parenchyma and in some cases, it\ncan manifest within the meninges of the brain . The aetio-\nlogical factors influencing the onset of endometriosis are\nretrograde menstruation, coelemic metaplasia,\nhaematogenic and lymphatic spread, remnants of the Mul-\nlerian ducts and various interleukins and growth factors\nproduced within the endometrial stromal or progenitor\ncells. The prevalence of the disease is varied due to the\nheterogeneous clinical manifestations, which include\ndysmenorrhea, dyspareunia, dysuria and chronic or severe\nlong-lasting abdominal pain, and in some cases infertility\nleading to a severe limitation in the quality of life. [2, 3]\nThe development of endometriosis is proposed as retro-\ngrade menstruation, which is, in fact, where the menstrual\nblood and uterine tissues enter the peritoneal cavity by way\nof the fallopian tubes . [4] However, in more than 90% of\nwomen participating in investigations such as laparoscopy,\nit has been revealed that, in fact, the theory of retrograde\nmenstruation facilitated the transport of endometrial tissue\nto the peritoneal cavity; however, an external factor is re-\nsponsible for increasing the susceptibility of certain women\nto experience this implantation and growth of this ectopic\nendometrium. [5] Within this, other theories have been\nsuggested, such as an altered peritoneal environment, im-\nmunological susceptibility and a greater amount of retro-\ngrade menstruation and not to mention the influence of ge-\nnetic predisposition, which can increase the likelihood of\nthis atypical process of endometriosis to occur. In addition\nhttps://doi.org/10.5272/jimab.2024301.5323\n\n5324 https://www.journal-imab-bg.org J of IMAB. 2024 Jan-Mar;30(1)\nto this, it can be proposed that the undergoing of prolif-\neration, secretion, regression and regeneration of the en-\ndometrial lining of the uterus during the period of the men-\nstrual cycle can influence the pathological atypicality of\nthe endometrium in subtle alterations in the events that\ntake place during the menstrual phase. One of the main\ntheories includes the ability of the endometrium to divide\nand, hence, the resulting implantation and growth within\nthe peritoneal cavity. Furthermore, within the complex se-\nries of events that arise within the menstrual cycle, the role\nof blood vessel proliferation and stimulation of endome-\ntrial gland development is important, and three different\nseparate episodes of angiogenesis of blood vessels have\nbeen proposed and comprise of post-menstrual repair dur-\ning the early proliferative phase, mid-proliferative phase\ngrowth under the direct influence of oestrogen and growth\nof the coiling of the spiral arteries and arterioles situated\nin the stratum functionalis of the endometrium which is in-\nfluences by the presence and production of progesterone\nvia the corpus luteum in the secretory or luteal phase of\nthe menstrual cycle. [6] The presence of angiogenesis\nwithin the endometrium can be denoted via laparoscopy,\nand findings include dense vascularization. In early le-\nsions, blood vessels appear pink-red with a high blood ves-\nsel density, dilated vascular structures and an increased\nnumber of immature vessels when compared with black le-\nsions and a general increase in vascularization surround-\ning the area of abnormal vessel geography. Researchers and\nspecialists within this field have been investigating the\nangiogenetic processes within the endometrium in order to\ndevelop anti-angiogenetic treatment strategies, which may\nreduce the side effects and recurrences seen in women un-\ndergoing conventional conservative therapies or main-\nstream surgical treatment. This review article will look at\nthe angiogenetic factors and pathophysiological processes\nthat occur within the endometrium and whether this infor-\nmation is sufficient in the diagnosis and treatment of en-\ndometriosis. [7, 8]\nMATERIALS AND METHODS\nWe conducted a review of the available scientific lit-\nerature at Pub Med, Google, Science Direct, which included\nrandomized trials, prospective controlled trials, research\nreports and guidelines in the approach taken in the research\nof angiogenetic factors influencing endometriosis in terms\nof development and clinical application of treatment strat-\negies involving angiogenetic factors. In the Scientific lit-\nerature, we searched for outcomes that included Endome-\ntriosis, Pathophysiology of Endometriosis, therapy of en-\ndometriosis, angiogenetic factors, angiogenetic theories\nproposed in the process of endometriosis. We have also in-\ncluded research and analysis of conventional treatment\nmethods utilized in the treatment of endometriosis that may\nhave an impact on the development of angiogenetic factor\ntreatment therapies, which can be used in treating endome-\ntriosis.\nDISCUSSION\nOur review of the scientific literature indicated evi-\ndence of the importance of angiogenetic processes within\nthe pathophysiological development of endometriosis and\nwhether new mainstream forms of treatment can be devel-\noped based on the proposed theories to revolutionize the\nway obstetricians and gynaecologists treat women suffer-\ning from this disease.\nObstetrics and gynaecology is a medical speciality\nwhich is widely needed as it is a dual-speciality both work-\ning to keep pregnancies healthy whilst being responsible\nfor the delivery of viable foetuses, and it also focuses on\nthe broader spectrum of issues relevant to a woman, spe-\ncifically the health and disease manifestation of the female\nreproductive system. A normal endometrial lining of the\nuterus, the proposed mechanism of angiogenesis occurs in\nthe form of vessel elongation rather than a branch spout-\ning of the spiral arteries, and it is the primary mechanism\nfor development and growth of the endometrium during the\nfirst 14 days of the menstrual cycle namely known as the\nproliferative phase. However, it seems that there is a recruit-\nment of new capillaries from existing adjacent peritoneal\nmicrovessels in conjunction with this, it is also essential\nto mention the importance of the newly synthesized blood\nvessels derived from the circulation endothelial progeni-\ntor cells in a process called vasculogenesis, which is also\ninvolved in the pathogenesis of endometriosis. The en-\ndometrium is a dynamic tissue which displays various prop-\nerties, such as populations of clonogenic epithelial and stro-\nmal stem cells that require indefinitely active cyclical an-\ngiogenesis. [9, 10]\nEndometriosis can produce various chemotactic fac-\ntors, such as cytokines and growth factors, that regulate\ntheir proliferation and vascularization. Interleukin-1 Beta\nis an important interleukin-1 secreted by the peritoneal\nmacrophages, and it plays a pivotal part in the\nneovascularization of the endometriotic like lesions. In ad-\ndition to this, IL-6 is a multi-subunit and multifunctional\nprotein which promotes endometrial cellular proliferation\nand angiogenesis, and its production is elevated in en-\ndometriosis and the concentrations of IL-6 can be found\nin high quantities in the peritoneal fluid of such individu-\nals. IL-8 is worth mentioning as it is a pro-inflammatory\ncytokine that induces the chemotaxis of neutrophils and\nhas a potent stimulatory effect on the angiogenetic mecha-\nnism. The presence of IL-1B influences and increases the\nangiogenetic factors in neutrophils to stimulate endome-\ntriosis-associated angiogenesis. On the other hand, in the\npresence of specific transcription factors, hypoxic-induc-\nible factors enhance the expression of pro-angiogenetic fac-\ntors like VEGF to induce hypoxia-induced angiogenesis.\nIn the presence of transcriptional factor HIF-1 alpha, VEGF\nm-rna expression levels increase in response to hypoxia;\nmoreover, the HIF-1 alpha factor is responsible for regulat-\ning the expression of transcriptional genes encoded in the\ntranscriptional synthesis of VEGF to induce hypoxemic-in-\nduced angiogenesis. [11]\n\nJ of IMAB. 2024 Jan-Mar;30(1) https://www.journal-imab-bg.org 5325\nActivin A is a growth factor member of TGF-beta\nwith subsequent effects on inflammation and angiogenesis.\nThe human endometrium is both a source and target of\nActivin A, and it can both up and down-regulate the ex-\npression and secretion of IL-8 and vascular endothelial\ngrowth factor, which are produced from the endothelial stro-\nmal cells. Consequently, the vascular growth factor is the\nmost potent and specific angiogenetic factor responsible\nfor a variety of effects such as endothelial cell prolifera-\ntion and migration, organization of endothelial cells into\ntubular like structures, and incr ease in permeability, all of\nwhich participate in the endometrial angiogenetic cascade.\nThe basis of the so-called vascular endothelial growth fac-\ntor is influenced by the presence and levels of oestrogen,\nwhich in the late proliferative phase of the menstrual cy-\ncle increases in quantity VEGF to promote the prolifera-\ntion and neovascularization of the endometrium in order\nto prepare the endometrial lining of the uterus for concep-\ntion and implantation of the blastocyst which is being\nbrought in via the fallopian tubes from the ovaries, how-\never, it is important to note that the concentration of VEGF\nis at its peak in the secretory phase and phase of menses .\nAngiogenesis can occur throughout fetal growth and\ndevelopment, but in adults, it is concentrated in the men-\nstrual cycle, the ovaries in the liberation of the mature\ngraafian follicle and formation of corpus luteum and in vari-\nous pathological conditions such as wound healing, dia-\nbetic retinopathy, tumour growth and not to mention en-\ndometriosis. Specifically within the menstrual cycle, the\nprocess of angiogenesis plays a crucial role in the follicular\nmaturation development of a functional corpus luteum. The\nimportance of angiogenesis within endometriosis is such\nthat the nova vasculogenesis that takes place from pre-ex-\nisting blood vessels is necessary for the survival and pro-\ngression of ectopic endometrial tissue situated outside of\nthe uterine cavity. Oestrogen is an important hormone\nwithin the menstrual cycle and plays an important role in\nthe development of blood vessels for endometriotic im-\nplants. The 17-Beta estradiol up-regulates the VEGF expres-\nsion in the endometrial human stromal cells by activating\nthe Wnt/B-catenin axis through estrogenic receptors and\nthus enhances their ability to establish a new blood sup-\nply to the endometrium. Furthermore, estrogenic receptors\nof the beta sub-type directly regulate the expression of\ngenes involved in hypoxia-induced angiogenesis, such as\nHIF-1 alpha, VEGF, angiotensin 1 receptors in ectopic le-\nsions of the endometrium to support the progression of en-\ndometriosis. In addition to this, there are various other fac-\ntors which interact with one another to up-regulate or in-\nhibit the activation of VEGF within the endometrial tissue.\nFor example, peptide hormones regulate angiogenesis by\nstimulation or inhibition to promote or prevent the growth\nof the ectopic tissue and through the process of proteoly-\nsis, we have a conversion of the original hormone into ei-\nther a pro-angiogenetic peptide, which is a stimulating fac-\ntor in the progression of ectopic endometrial tissue, or it\ncan lead to anti-angiogenic peptide formation which acts\nin an inhibitory form preventing the progression of ectopic\nendometrial tissue .\nFurthermore, if we look at the findings, it demon-\nstrates that angiogenesis within endometriosis is influenced\nby an interaction of various intra and extracellular signal-\nling molecules, which interact with one another and are in-\nfluenced by local hypoxic and inflammatory stimuli within\nthe specific microenvironment of the peritoneal cavity. The\nability to determine the type of transcriptional factors and\nhormonal elements and the extent of influence of endome-\ntriosis is very difficult because different endometrial phe-\nnotypes markedly have different levels of genetic expres-\nsion levels of genes associated with hypoxia and angio-\ngenesis. With regards to endometriosis and the influence\nof angiogenesis on a clinical basis, we can say that within\nthe role of angiogenesis and influence over the progres-\nsion of endometriosis is reflected in the fact that the peri-\ntoneal fluid from endometriosis patients significantly in-\ncreases the proliferation of endothelial cells and induces a\nstrong vascular reaction leading to new blood vessel for-\nmation within the ectopic tissue of endometrium type. This\nis due to the fact that peritoneal fluid contains elevated\nconcentrations of different angiogenetic promoting factors\nsuch as VEGF, insulin growth factor 1, angiotensin-2, eryth-\nropoietin, hepatocyte growth factor and on the other hand\nthe peritoneal fluid also contains lower concentrations of\nanti-angiogenetic factors namely adiponectin, interferon-\ngamma induced protein-10. These findings are interesting\nas they serve as a basis that when diagnosing endometrio-\nsis, we may be able to use the interaction of these pro and\nanti-angiogenetic factors as biomarkers for determining a\nworking diagnosis of endometriosis as well as for assess-\ning the efficacy of therapeutic approaches taken to treat\nendometriosis. However, although promising studies have\nindicated a positive indication of these factors as\nbiomarkers in endometriosis, as of yet, they are of insuffi-\ncient diagnostic sensitivity and specificity. This can be ex-\nplained by the low study sample or the heterogeneous dis-\neases stages of the subjects within the study sample. To fur-\nther this, it is important to use a combination of biomarkers\nto diagnosis endometriosis. Currently, such proposals for\nutilizing these tools can only be used to assess the risk of\ndeveloping endometriosis or adenomyosis. [12, 13] In line\nwith the proposal to use medicinal compounds containing\nanti-angiogenetic constituents, it has shown to be a prom-\nising target for gene therapy or pharmacological-based\ntreatment of endometriosis. These include growth factor in-\nhibitors, endogenous angiogenesis inhibitors, fumagillin\nanalogues and statins, immunomodulators in which these\nmedicaments have been proven to reduce the micro vessel\ndensity of endometriotic lesions in animal models with a\nresulting effect of engrafted lesions or a suppressed lesion\ngrowth. In studies carried out on mice, the concept of treat-\nment containing angiogenetic compounds, the blood ves-\nsels invading the endometrium are accompanied by nerve\nfibres. These nerve fibres stimulate the dorsal root neurons\nwithin the central nervous system, which increases the pain\nperception in endometriosis patients. Due to this finding,\nthe treatment of endometriosis with anti-angiogenetic com-\npounds not only leads to a reduction of blood vessel for-\nmation but also nerve fibre growth in the ectopic tissue.\n\n5326 https://www.journal-imab-bg.org J of IMAB. 2024 Jan-Mar;30(1)\nDespite the promising results, anti-angiogenic therapy has\nnot been implemented for clinical use because of several\nreasons. The first is because endometriosis is a heteroge-\nneous disease with diverse types of lesions in different lo-\ncations, and so each location containing ectopic endome-\ntrial tissue will have a varying degree of vascularization\nand composition. Anti-angiogenic compounds target the\nearly red lesions with a high level of angiogenic activity\nand immature micro vessels, so the older, black and white\nlesions may be resistant to this form of treatment. Thus, the\nadministration of anti-angiogenic compounds may not be\nsuitable as a monotherapeutic drug focusing on pharma-\ncological-based eradication as well as eradication of well-\nestablished endometriotic lesions in the peritoneal cavity.\nHowever, the anti-angiogenic compounds may serve as an\nimportance in the prevention of new lesion formation after\nsurgical removal and, therefore, can help to reduce high\nrecurrence rates of surgical based endometriosis therapies.\nIn addition to this, the resistance to anti-angiogenic drugs\nposes an issue with the usage of anti-angiogenic com-\npounds, but this can be overcome by simultaneously sup-\npressing different angiogenic compounds or by means of\ncombination therapy. Finally, the women who suffer from\nendometriosis are of reproductive age and may wish to pre-\nserve their fertility; this poses as a problem as the fertility\nand uterus are heavily dependent upon the physiological\nangiogenesis in the ovary, uterus and placenta and, there-\nfore, the long-term administration of anti-angiogenic agents\nis contraindicated due to the unknown effects on the fe-\nmale reproductive organs which may compromise the ability\nof the women to conceive and bear a child should the fe-\nmale have the desire or wish to have children. In order to\novercome this, trials are currently being carried out utiliz-\ning anti-angiogenic agents with a more acceptable and safe\nprofile to see whether the same adverse effects are produced\nor if milder side effects are present, which can be contained\nwith combined therapy. [14]\nAnti-angiogenic agents are agents which block the\naction of VEGF and inhibit the ability of VEGF to initiate\narteriole proliferation and neogenesis. Bevacizumab is a\nrecombinant human monoclonal antibody that inhibits\nVEGF, inhibiting the development and proliferation of\nendometriotic lesions with a reduction in the vascular den-\nsity and increased apoptosis with a reduction of VEGF lev-\nels in the peritoneal fluid. Sorafenib is another anti-ang-\niogenic agent, which in its form is an orally active\nmultikinase inhibitor that interferes with the activity of the\nVEGF receptor and tyrosine kinase receptors, and in the\nmice model, it reduces the micro vessel density and lesion\nvolume in patients suffering from endometriosis. Lipoxin\nA4 is an endogenous eicosanoid whose role is to regulate\ninflammation. This lipid-based medicament blocks the mi-\ngration of endothelial cells and VEGF-stimulated angiogen-\nesis. The Lipoxin A4 r educes the endometrial lesion size\nand down regulates the inflammation-associated proteins\nsuch as IL-6, VEGF and matrix metalloproteinase 9.\nParecoxib, a selective cyclooxygenase-2 inhibitor, reduces\nthe lesion size, micro vessel density, the number of\nmacrophages and the expression of VEGF, which leads to\natrophy and regression of endometrial ectopic tissues when\ncarried out on mice. Statins are inhibitors of HmG-COA\nwith an intrinsic antioxidant, anti-inflammatory and anti-\nangiogenic properties, f or example, Atorvastatin inhibited\nthe inflammatory and angiogenetic genes COX-2 and\nVEGF in endometrial stromal cells. Another important anti-\nangiogenic agent is the dopamine agonist cabergoline,\nwhich exerts its effect thr ough VEGFR-2 inactivation, in-\nhibiting the growth of established endometrial lesions. Fi-\nnally, progestogens reduce the proliferation of endometrial\nstromal cells and suppress the transcription of VEGF-A and\nthe microvessel density in human ectopic endometrial le-\nsions. [15, 16]\nCONCLUSION\nWithin the last decade, it has become evident that\nthe process of angiogenesis plays a central role in the\npathogenesis of endometriosis. Many angiogenetic induc-\ning factors can be determined, such as VEGF, which is\npresent in peritoneal fluid and ectopic endometrial tissue\nfrom endometriotic patients. However, despite all of this,\nthere is still limited evidence in the knowledge of under-\nstanding the mechanisms behind blood vessel angiogen-\nesis and the complex and dynamic interactions between\nvarious factors and pathophysiological processes which\nwork together to regulate angiogenesis specifically within\nthe endometrium. To conclude, more research is needed on\nthe mechanisms of angiogenesis and the general physiologi-\ncal process of developing new blood vessels within the en-\ndometrial ectopic tissue to ascertain a broader and more\ncomplete understanding of endometriosis.\n\nJ of IMAB. 2024 Jan-Mar;30(1) https://www.journal-imab-bg.org 5327\n1. Rocha AL, Reis FM, Taylor RN.\nAngiogenesis and endometriosis.\nObstet Gynecol Int.  2013;2013:\n859619. [\nPubMed ]\n2. Krikun G. Endometriosis, ang-\niogenesis and tissue factor.\nScientifica (Cairo).  2012;2012:\n306830. [\nPubMed ]\n3. Qiu JJ, Lin XJ, Zheng TT, Tang\nXY , Zhang Y , Hua KQ. The Exosomal\nLong Noncoding RNA aHIF is\nUpregulated in Serum From Patients\nWith Endometriosis and Promotes An-\ngiogenesis in Endometriosis. Reprod\nSci . 2019 Dec;26(12):1590-1602.\n[\nPubMed ]\n4. Vinatier D, Orazi G, Cosson M,\nDufour P. Theories of endometriosis.\nEur J Obstet Gynecol Reprod Biol.\n2001 May;96(1):21-34. [\nPubMed ]\n5. 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[\nPubMed ]\nAddress for correspondence:\nNikolay Lazarov\nDepartment of Obstetrics and Gynaecology, Medical Faculty, Trakia Univer-\nsity, Stara Zagora;\n11, Armejska Street, Stara Zagora, Bulgaria.\nE-mail: n.lazaroff@gmail.com\nPlease cite this ar ticle as:  Lazarov N, Saghir F. An Insight into Endometriosis: Role and Influence of the Process of\nAngiogenesis. J of IMAB.  2024 Jan-Mar;30(1):5323-5327. [Crossref - https://doi.org/10.5272/jimab.2024301.5323 ]\nReceived: 15/06/2023; Published online: 23/01/2024","source_license":"CC0","license_restricted":false}