O-100:Endometrial Angiogenesis:Physiology And Pathology

The functionalis layer of human endometrium is a highly dynamic tissue, undergoing dramatic cyclical remodeling throughout a woman’s reproductive life. The uterine lining typically grows from a thickness of 0.5 mm in the postmenstrual phase to >5 mm in the late proliferative and secretory phases of the endometrial cycle. The robust proliferation of endometrial epithelial and stromal cells is accompanied pari passu by extensive vascular and capillary growth, which provides the oxygen and nutrients needed to support the cyclic tissue expansion. Excessive angiogenesis is associated with endometrial polyps and neoplasia, whereas reduced angiogenesis appears to lead to defects in endometrial receptivity, embryonic loss and pregnancy complications associated with failed placentation. Our laboratory has been interested in the endocrine factors that mediate capillary proliferation in the human uterus and we have focused predominantly of the role of vascular endothelial growth factor (VEGF). This gene product is the most potent mitogen for capillary endothelial cells and it is highly expressed in endometrial epithelial and stromal cells. We have determined that the human VEGF gene is under direct transcriptional control by estrogen receptor complexes liganded to 17-beta estradiol (E2) or synthetic estrogens. We identified a unique variant estrogen responsive element in the human VEGF gene promoter that mediates the stimulatory effects of estrogens on VEGF production in endometrial cells. Progesterone (P4) also imposes proangiogenic effects on endometrial cells via the upregulation of VEGF gene and protein expression, although its mechanism of action is more mysterious. Unbalanced progestins may contribute to abnormal uterine bleeding associated with contraceptives. The combination of E2 and P4, as observed in the midluteal window of implantation appears to optimize the vasculature for embryonic receptivity. By contrast, anti-angiogeneic therapeutics may be useful in conditions associated with excessive endometrial vascular growth, such as polyps, endometriosis or contraceptive breakthrough bleeding.