application) This proposal will examine mechanisms by which estrogen modulates responses to vascular injury. The PI's group has shown that the myointimal response to balloon injury of rat carotid and pig coronary arteries are greatly reduced in female compared to male animals and that systemic administration of exogenous estrogen, beginning prior to injury and continuing throughout the post -injury period, blunts the injury response in gonadectomized animals of both sexes. The hypothesis of the current proposal is that estrogen inhibits responses to vascular injury via mechanisms that involve direct inhibition of vascular smooth muscle cell proliferation, stimulation of re-endothelialization and recovery of endothelial cell function.
Specific aim 1 will test the hypothesis that estrogen prevents the myointimal response to carotid artery injury in the rat by direct, receptor mediated effects that involve reduced expression of the early response protooncogene c-myc. Experiments will test whether the myointimal proliferative response and c-myc expression are prevented by the naturally occurring estrogen, 17beta-estradiol administered short-term s.c. or locally to the adventitial surface of the injured artery, or by the selective estrogen receptor agonist raloxifene. The effects of the selective estrogen receptor antagonist ICI-182780 will also be examined.
Aim 2 will test the hypothesis that progesterone blunts the protective effects of estrogen on the carotid injury response.
Aim 3 will examine the cellular mechanisms of the interactions between progesterone, androgen, and estrogen on cultured vascular smooth muscle cells and endothelial cells from rat and human aortas.
Specific aim 4 will test the hypothesis that estrogen accelerates re-endothelialization and restores endothelial function in the balloon injured carotid artery of the rat, and that enhanced re-endothelialization can be related to a blunted myointimal proliferative response to injury.
