Ischemic vascular diseases are the leading cause of morbidity and mortality in women in our society, but are uncommon prior to menopause. In addition, post-menopausal estrogen replacement decreases vascular events in women. It is now appreciated that estrogen has direct effects on the blood vessel wall that likely contribute to the differences in vascular diseases and their treatment between men and women. Our laboratory has recently (i) demonstrated human vascular smooth muscle cells contain a functional estrogen receptor; (ii) identified novel estrogen-regulated genes in vascular smooth muscle cells; and (iii) shown that physiologic estrogen replacement markedly suppresses the vascular response-to-injury in a mouse carotid artery model. These data support the hypothesis that estrogen inhibits smooth muscle cell proliferation following vascular injury via estrogen receptor-mediated changes in endothelial cell and/or vascular smooth muscle cell gene expression.
The Specific Aims of this proposal include: (1) Investigation of the mechanism by which estrogen inhibits the response-to injury in the mouse carotid model, using morphometric, immunohistochemical, biochemical and molecular methods to study (a) the effects of estrogen on endothelial cell growth; (b) the carotid response-to-injury in transgenic mice in which the estrogen receptor has been disrupted; (c) the effect of estrogen receptor antagonists on estrogen inhibition of vascular injury; and (d) the effects of estrogen on carotid injury in normal and transgenic male mice; (2) Investigation of the mechanisms by which estrogen inhibits the response-to-injury in the porcine femoral injury model using morphometric, immunohistochemical, and molecular methods to study the effects of estrogen on vascular cell growth and the injury response; and (3) Further investigation of the molecular mechanisms of estrogen's inhibitory effects in cells and vascular tissue from these animal studies, including (a) study of vascular endothelial growth factor (VEGF) in vascular tissue from the murine and porcine studies, using immunohistochemistry and in situ hybridization; (b) study of both hormone-independent (TAF-1 domain) and hormone-dependent (TAF-2 domain) estrogen receptor activation of the VEGF gene in vascular cells; and (c) use of subtractive hybridization methods to identify novel estrogen-regulated genes from cells and tissues obtained in the animal experiments. These studies will contribute to our understanding of molecular mechanisms important in the vascular injury response, and to our understanding of the pathophysiology and treatment of vascular disorders in both women and men.
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