Abstract-Multiple lines of evidence suggest that estrogen directly modulates angiogenesis via effects on endothelial cells.Under physiological conditions, angiogenesis is routinely observed in the uterus in association with fluctuations in the levels of circulating estradiol and other sex steroids. In pathological circumstances, such as breast cancer, a clear association between estrogen, estrogen receptor expression by endothelial cells, angiogenic activity, and/or tumor invasiveness has been made. Studies performed in our laboratory have revealed that estradiol accelerates functional endothelial recovery after arterial injury. Despite these consistent observations, the mechanisms by which estrogen regulates angiogenesis under physiological and pathological circumstances have not been defined. Key Words: estrogen Ⅲ angiogenesis Ⅲ vasculogenesis Ⅲ endothelium Ⅲ endothelial progenitor cells I n adult organisms, angiogenesis is virtually absent under normal conditions, except in the female reproductive tract. This observation suggests the potential for sex steroids to influence neovascularization. Several other associations, including the predilection of certain diseases (such as Takayasu's arteritis and lupus, both of which involve endothelial cell proliferation) for premenopausal females, also imply the potential role of estrogen in angiogenesis. 1,2 The role of estradiol in uterine angiogenesis, mediated by at least 1 of the estrogen receptors, has been further suggested by findings in the estrogen receptor-␣ knockout mouse, in which angiogenesis is impaired, 3 and by the demonstration that estrogen receptor antagonists can inhibit angiogenesis. 4 The positive correlation between estrogen receptor expression, angiogenic activity, and breast tumor invasiveness also supports the angiogenic effect of estrogen mediated by the estrogen receptor(s). [5][6][7][8] Finally, some reports suggest that the antitumor effect of tamoxifen may in fact relate to an antiangiogenic action of this estrogen receptor agonist/antagonist. 9 Several additional lines of experimental evidence suggest that estrogen and other sex steroids play important roles in physiological and pathological angiogenesis. One of the first observations suggesting a hormonal influence on angiogenesis was an inhibitory effect on tumor vascularization by medroxyprogesterone. 10 Subsequent studies have indicated that the mechanism of this inhibition may relate to the regulation of thrombospondin-1, an angiogenesis inhibitor, by this hormone. 11 Angiogenesis has been noted to be a prognostic marker in breast cancer, 12 and inhibition of angiogenesis in these tumors has been effected by antiestrogens. 4 In addition, the estrogen metabolite 2-methoxyestradiol has been shown to be a potent antiangiogenic agent 13 mediated by actions on cytoskeletal structure 14 and by increasing endothelial cell apoptosis. 15,16
Vascular Endothelial Cell Proliferation and Migration Are Enhanced by EstradiolEstradiol induces endothelial proliferation and migration 17 mediated by t...