Inflammation plays an important role in the pathogenesis of many forms of vascular disease, and menopausal hormone therapy has been shown to modulate the expression of inflammatory biomarkers in women. This proposal will utilize a well-characterized rodent model to elucidate the fundamental cellular/molecular mechanisms by which ovarian hormones, particularly estrogen (E2), modulate the inflammatory response to acute endoluminal vascular injury. Our preliminary studies have demonstrated extensive inflammatory cell infiltration and increased expression of a variety of proinflammatory mediators in carotid arteries of ovariectomized rats within hours after balloon injury. We have made the novel and provocative preliminary observation that E2 inhibits granulocyte and monocyte/macrophage infiltration, as well as proinflammatory mediator expression in injured arteries. The synthetic progestin medroxyprogesterone acetate (MPA) blocks this anti-inflammatory effect. We have also observed that E2 inhibits expression of chemokines known to be chemoattractant for leukocytes in vascular smooth muscle cells (VSMCs) in vitro. The proposed research, based on these exciting and provocative preliminary observations, as well as our extensive experience in studying ovarian hormone-induced modulation of the vascular injury response, will identify the inflammatory cell types whose activation/migration can be modulated by ovarian hormones and will define the signaling cascade by which these cells direct the response to endoluminal arterial injury in the presence and absence of ovarian hormones. Novel highly selective (subtype specific) and potent agonists and antagonists of estrogen receptors (ERalpha and ERbeta), RNA interference technology and microarray analyses will be used to provide a rigorous assessment of the functional role of anti-inflammatory mechanisms in mediating the vasoprotective effects of E2 in this model. Upon successful completion of the proposed research, the cellular/molecular mechanisms responsible for the anti-inflammatory effects of E2 on injured arteries and their inhibition by MPA will be elucidated and related to the extent of the injury response (i.e. neointima formation). These fundamental mechanistic studies will enhance our understanding of the pathobiology of vascular disease, particularly as it occurs in aging women, and will provide the basis for development of novel therapeutic strategies.
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