Upregulation of Endocrine Gland-Derived Vascular Endothelial Growth Factor, But Not Vascular Endothelial Growth Factor in Human Ectopic Endometriotic Tissue

Previous studies have shown that the expression of vascular endothelial growth factor (VEGF) is critical for the development and growth of transplanted endometriosis-like lesions in mouse model systems. The angiogenic response induced by another growth factor, endocrine gland-derived VEGF (EG-VEGF), in the ovary is indistinguishable from that by VEGF. Also known as prokineticin 1 (PK1), EG-VEGF acts through G-protein coupled receptors, PKR1 and PKR2. It is upregulated in the periimplantation endometrium after gonadotropin stimulation and hormone replacement therapy. Some investigators believe that increased expression of EG-VEGF messenger RNA (mRNA) and protein in ectopic endometriotic tissues may be associated with the progression of the disease. The function of EG-VEGF in the uterus is largely unknown and its role in endometriosis is unclear. The aim of this case–control study was to investigate the expression of VEGF, EG-VEGF, and their receptors (PKR1 and PKR2) in eutopic and ectopic endometrial tissues. The investigators hypothesized that aberrant expression of EG-VEGF could be important to the pathogenesis of endometriosis. The subjects for study were infertile women with endometriosis; who were undergoing diagnostic laparoscopy for assessment of tubal patency. Samples of endometrial and endometriotic tissues were taken from women with and without endometriosis. The biopsied tissues were analyzed by quantitative real-time polymerase chain reaction analysis to compare mRNA expression in eutopic and ectopic endometrial tissues. Immunohistochemical staining (using H scoring) was used to determine the expression of EG-VEGF protein in 12 pairs of endometriotic samples. The expression of EG-VEGF mRNA in normal endometrium was 50-fold higher in the secretory than in the proliferative phase; mRNA expression in the PKR1 was 6-fold higher in the proliferative than in the secretory phase. The PKR2 transcript was detected in the normal proliferative but not in the normal secretory endometrium. The expression of eutopic PKR2 mRNA from patients with endometrioisis was 4-fold higher in the proliferative than in the secretory endometrium; no differences were noted in EG-VEGF and PKR1 expression between the proliferative and secretory eutopic endometria. Comparison of the normal and the endometriosis groups showed no significant difference in the expression of EG-VEGF in eutopic endometrium. Comparison of the eutopic and ectopic endometrial samples showed no significant difference in VEGF expression, whereas EG-VEGF expression was significantly higher for the ectopic samples. The expression of PKR1 and PKR2 was very low or undetectable. Higher H scores (more intense staining) were found in the stromal cells of ectopic endometriotic samples than in the paired eutopic endometrial samples; this was indicative of significantly higher EG-VEGF protein expression in the former. These findings suggest that EG-VEGF has an important role in ectopic endometrial angiogenesis and the pathogenesis of endometriosis.