The angiogenesis and changes in permeability that characterize the endometrial microvasculature may contribute to a number of serious diseases of the uterus.
Infertility: As discussed previously, changes in vascular permeability play a critical role in the preparation of the uterus for implantation and in the implantation process itself. Inadequate permeability, due to inadequacy of hormonal stimulation, the inability of the endometrium to react with appropriate VEGF expression, or failure of vessels to respond to VEGF, could give rise to a nonreceptive endometrium and failure of implantation. Infertility could also result from placental insufficiency. Hypoxia, one of the strongest inducers of VEGF expression, is believed to play an essential role in the growth of the placenta through maintenance of trophoblast cell proliferation . Furthermore, knockout of HIF-1, a key regulator of VEGF expression (below), blocks placentation.
Dysmenorrhea/uterine bleeding: VEGF mediates normal estrogen-induced endometrial development and vasculariza-tion [7, 8, 10]. Imbalances in VEGF expression or activity, therefore, could contribute to abnormal uterine bleeding. This is supported by the results of a recent clinical trial of the protein hormone relaxin for the treatment of progressive systemic sclerosis . Relaxin, like estrogen, is an ovarian hormone that stimulates VEGF expression in the uterus (although its role in uterine physiology is less well understood at this time). The most frequent adverse event reported during the trial was heavier-than-usual or irregular menstrual bleeding. The authors of the study attributed this effect to relaxin-induced overexpression of VEGF in the uterus. VEGF is also implicated in the formation of uterine fibroids (below), which are also a frequent cause of abnormal uterine bleeding.
Endometriosis: Endometriosis is the abnormal growth of endometrial tissue at ectopic sites in the peritoneal cavity. It is a major cause of infertility in women of reproductive age, as well as of severe pelvic pain. Establishment of the lesions presumably requires their ability to revascularize at ectopic sites. A wide range of studies have implicated VEGF in this. The increase in VEGF expression in the superficial endometrium just prior to shedding during menstruation may make fragments that enter the peritoneal cavity prone to implantation there . Estrogen, relaxin, and hypoxia could all be involved in the regulation of VEGF expression by endometriotic tissue.
Leiomyoma: Uterine leiomyomas (fibroids) are benign tumors of the uterus that occur in one third of women over the age of 30. Although they originate in the smooth muscle of the myometrium rather than the endometrium, they impinge upon the endometrium and cause abnormal uterine bleeding, infertility, and pregnancy loss. They are one of the most common indications for hysterectomy. The regulation of their growth, however, is poorly understood, but estrogen is undoubtedly involved. Angiogenesis is also hypothesized to play a role in their formation, which implicates VEGF in their etiology, and the expression of VEGF has been reported to be elevated in endometrium and myometrium of leiomyoma-bearing uteri.
Uterine cancer: Expression of VEGF is significantly increased in most tumors, including uterine cancers. Circulating levels of VEGF even correlate with uterine tumor stage and burden. This strongly suggests that VEGF is an important angiogenic factor in endometrial carcinoma. Inhibition of VEGF action is being actively pursued as a means of treatment of cancer and other pathologies characterized by angiogenesis, with some agents now in phase III trials for treatment of human tumors. Such drugs could also prove useful for the treatment of noncancerous endometrial disorders such as dysmenorrhea and endometriosis.
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