Estrogen Modulates Injury-Induced Inflammation

描述（由申请人提供）：炎症在多种血管疾病的发病机制中起着重要作用，绝经期激素治疗已被证明可以调节女性炎症生物标志物的表达。本研究将利用一个具有良好特征的啮齿动物模型来阐明卵巢激素，特别是雌激素（E2）调节急性腔内血管损伤炎症反应的基本细胞/分子机制。我们的初步研究表明，在切除卵巢的大鼠颈动脉球囊损伤后数小时内，炎症细胞广泛浸润，多种促炎介质的表达增加。我们已经做出了新颖的和具有挑衅性的初步观察，E2抑制粒细胞和单核细胞/巨噬细胞浸润，以及促炎介质在损伤动脉中的表达。合成黄体酮醋酸甲羟黄体酮（MPA）阻断这种抗炎作用。我们还观察到E2抑制体外血管平滑肌细胞（VSMCs）中已知的白细胞趋化因子的表达。基于这些令人兴奋和具有挑战性的初步观察，以及我们在研究卵巢激素诱导的血管损伤反应调节方面的丰富经验，本研究将确定激活/迁移可由卵巢激素调节的炎症细胞类型，并将定义这些细胞在卵巢激素存在和不存在的情况下指导腔内动脉损伤反应的信号级联。新型高选择性（亚型特异性）和强效雌激素受体（erα和erβ）激动剂和拮抗剂，RNA干扰技术和微阵列分析将用于在该模型中提供抗炎机制在介导E2血管保护作用中的功能作用的严格评估。在成功完成本研究后，将阐明E2对损伤动脉的抗炎作用及其受MPA抑制的细胞/分子机制，并将其与损伤反应（即新生内膜形成）的程度相关。这些基本的机制研究将增强我们对血管疾病的病理生物学的理解，特别是当它发生在老年妇女时，并将为开发新的治疗策略提供基础。

DESCRIPTION (provided by applicant): 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.