Vascular Surgery - Estrogen and the Injury Response

激素作用和激素替代疗法在血管生物学中的作用是一个非常感兴趣的领域，但仍然存在很大的争议。大多数研究人员现在倾向于这样一个假设，即血管疾病的演变性质使得启动雌激素治疗的时机至关重要，当女性在更年期期间或之后不久接受雌激素治疗时，就会看到保护作用，而不是太晚。现在公认的是，雌激素对心血管组织有直接作用，这是雌激素对血管疾病的大部分保护作用的原因。雌激素对血管系统的直接作用是由两种配体激活的转录因子--雌激素受体ER1和ER2介导的。这一竞争性更新申请建立在分子心脏病研究所与塔夫茨-新英格兰医学中心血管外科部门合作进行的十多年研究的基础上，在这些研究中，我们使用野生型(WT)和ER基因敲除(ERKO)动物以及分子、细胞和血管模型的组合来探索ER1和ER2在血管系统中的作用机制。到目前为止的工作已经加深了对ER在血管系统中作用的理解，并支持ER既介导了雌激素对血管张力的控制，也通过基因组和非基因组途径调节一氧化氮合酶亚型(eNOS，iNOS)，从而介导了雌激素对血管损伤和动脉粥样硬化的保护作用。然而，迄今为止的研究依赖于探索雌激素对小鼠模型的影响，在小鼠模型中，ER在早期胚胎(整个动物ER基因敲除小鼠)中被破坏，从而使体内所有组织和细胞中的ER从受孕中删除。目前的应用程序建议使用目前正在使用的令人兴奋的新的转基因小鼠来测试我们在过去十年中进化出的机制假说。这些小鼠及其组织和细胞能够从EC或VSMC中精确删除ER1或ER2，并为检验这一应用的核心假设提供了强有力的方法，这些假设包括：血管内皮细胞ER1调控eNOS的表达和活性；血管平滑肌细胞(VSMC)ER1介导雌激素抑制血管损伤和动脉粥样硬化期间的VSMC增殖；以及VSMC ER2控制编码调节VSMC张力的关键收缩蛋白的基因。在研究血管ER1和ER2在调节完整血管张力中的作用；(SA2)血管ER1和ER2在正常血脂动物的雌激素保护血管损伤反应中的作用；以及(SA3)血管ER1和ER2在动脉粥样硬化中的作用。这些研究有望大大加深我们对血管和血管生理学中表达的雌激素受体的分子和细胞生物学的了解，并对妇女健康领域和男女预防和治疗血管疾病的新疗法的开发产生重要影响。

The role of hormone action and hormone replacement therapy in vascular biology is an area of intense interest, but remains highly controversial. Most investigators now favor the hypothesis that the evolving nature of vascular disease makes critical the timing of initiation of estrogen therapy, with a protective effect seen when women receive estrogen during or soon after menopause, rather than much later. It is now well accepted that estrogen has direct effects on cardiovascular tissues that account for the majority of the protective effects of estrogen against vascular diseases. The direct effects of estrogen on the vasculature are mediated by two ligand-activated transcription factors, estrogen receptors ER1 and ER2. This competitive renewal application builds upon over a decade of research done by the Molecular Cardiology Research Institute in collaboration with the Vascular Surgery Division at Tufts-New England Medical Center, in which we have explored the mechanisms of ER1 and ER2 action in the vasculature using wild type (WT) and ER knockout (ERKO) animals, and a combination of molecular, cellular and vascular models. Work to date has refined the understanding of ER action in the vasculature and supports that ERs mediate both control of vascular tone by estrogen and the protective effects of estrogen on vascular injury and atherosclerosis, in part through regulation of NOS isoforms (eNOS, iNOS) by both genomic and non-genomic pathways. However, studies to date have relied on exploring estrogen effects in mouse models in which an ER is disrupted in the early embryo (whole animal ER knockout mice), so that the ER is deleted from conception in all tissues and cells of the body. The present application proposes to test the mechanistic hypotheses we have evolved over the past decade using exciting new genetically modified mice that are now in hand. These mice, and their tissues and cells, enable the precise deletion of ER1 or ER2 from either EC or VSMC and provide powerful approaches to testing the central hypotheses of this application that vascular endothelial cell ER1 regulates eNOS expression and activity; vascular smooth muscle cell (VSMC) ER1 mediates estrogen inhibition of VSMC proliferation during vascular injury and atherosclerosis; and VSMC ER2 controls genes encoding key contractile proteins regulating VSMC tone. These mechanisms are explored in 3 Specific Aims using intact animals, blood vessels and cells with VSMC- or EC-specific, induced deletions of ER1 or ER2 in studies of the (SA1) role of vascular ER1 and ER2 in the regulation of vascular tone in intact vessels; (SA2) role of vascular ER1 and ER2 in estrogen protection of the vascular injury response in normolipidemic animals; and (SA3) role of vascular ER1 and ER2 in atherosclerosis. These studies are expected to add substantially to our understanding of the molecular and cellular biology of ERs expressed in the blood vessel and vascular physiology, with important impact on the field of women's health and on the development of new therapies for the prevention and treatment of vascular diseases in both women and men.