The Role of Vascular MR-Regulated Genes in Vascular Function and Disease

 描述（由申请人提供）：醛固酮激活肾脏中的盐皮质激素受体（MR），以调节钠处理和血压（BP）。醛固酮升高在包括顽固性高血压、肥胖和心力衰竭在内的不断增长的人群中很常见，并可预测这些患者发生心肌梗死（MI）、中风和死亡的风险。MR拮抗剂可防止这些与血压变化不成比例的结局，从而导致本项目的总体假设：血管MR直接导致血管功能和心血管疾病（CVD），并且血管MR控制的基因和途径的鉴定将确定CVD的新机制和治疗靶点。结果表明，人血管平滑肌细胞（SMC）和内皮细胞（EC）中存在功能性MR。在前5年中，我们专注于SMC-MR，我们的发现，包括血管重塑的新机制以及SMC-MR在衰老过程中调节血压的直接作用，极大地改变了我们的MR生物学和CVD机制的范式。在接下来的4年里，我们将探讨EC-MR在CVD中的作用.为此目的，我们产生了一种创新的小鼠模型，其中MR特异性地从EC（而不是白细胞）缺失，并发现EC-MR缺失可预防肥胖和高脂血症诱导的内皮功能障碍。我们建议使用这种EC-MR-KO小鼠来测试新的假设，即EC-MR有助于内皮功能障碍、血管炎症和动脉粥样硬化进展的发展，特别是在存在心脏危险因素如肥胖、高血压和高脂血症的情况下。我们提出三个目标：1）使用来自暴露于心脏危险因素的EC-MR-KO和MR-完整小鼠的肠系膜血管丝肌造影术确定EC-MR在将心脏危险因素传递到内皮功能障碍中的作用; 2）探索EC-MR增强血管炎症的机制。使用体外平行板流动室测定，我们发现EC-MR增强T细胞通过EC的粘附和迁移，并且我们提出使用流式细胞术和活体显微镜检查体外和体内的机制;和3）使用EC-MR-KO小鼠与动脉粥样硬化易感ApoE-KO小鼠杂交检查EC-MR在动脉粥样硬化中的作用。拟议的研究使用创新的小鼠模型来推进我们对常见风险因素导致CVD的机制的理解。这些目标的完成将为高醛固酮人群（心力衰竭、肥胖、耐HTN、低钠饮食）心血管缺血风险增加以及高醛固酮对血管的保护作用提供机制解释。 MR拮抗剂。此外，这些研究有望确定新的治疗靶点，以预防这些快速增长和高风险人群中的心血管缺血。

 DESCRIPTION (provided by applicant): Aldosterone activates mineralocorticoid receptors (MR) in the kidney to regulate sodium handling and blood pressure (BP). Elevated aldosterone is common in growing populations including resistant hypertension, obesity, and heart failure and predicts the risk of myocardial infarction (MI), stroke and death in these patients. MR antagonists prevent these outcomes out of proportion to BP changes leading to the overarching hypothesis of this program: that vascular MR contributes directly to vascular function and cardiovascular disease (CVD) and that identification of the genes and pathways controlled by vascular MR will identify novel mechanisms and therapeutic targets for CVD. We showed that functional MRs exists in human vascular smooth muscle cells (SMC) and endothelial cells (EC). In the first 5 years we focused on SMC-MR and our discoveries, including a novel mechanism for vascular remodeling and a direct role for SMC-MR in BP regulation with aging, have dramatically changed our paradigm of MR biology and mechanisms of CVD. In the next 4 years, we propose to explore the controversial role of EC- MR in CVD. For this purpose, we generated an innovative mouse model with MR specifically deleted from ECs (and not leukocytes) and found that EC-MR deletion prevents obesity- and hyperlipidemia- induced endothelial dysfunction. We propose to use this EC-MR-KO mouse to test the novel hypothesis that EC-MR contributes to the development of endothelial dysfunction, vascular inflammation, and atherosclerosis progression specifically in the presence of cardiac risk factors such as obesity, high BP, and hyperlipidemia. We propose 3 aims: 1) Determining the role of EC-MR in transmitting cardiac risk factors into endothelial dysfunction using mesenteric vessel wire myography from EC-MR-KO and MR- intact mice exposed to cardiac risk factors; 2) Exploring the mechanism by which EC-MR enhances vascular inflammation. Using in vitro parallel plate flow chamber assays, we found that EC-MR enhances T cell adhesion and migration through ECs and we propose to examine the mechanisms both in vitro and also in vivo using flow cytometry and intravital microscopy; and 3) Examining the role of EC-MR in atherosclerosis using EC-MR-KO mice crossed with atherosclerosis-prone ApoE-KO mice. The proposed studies use innovative mouse models to advance our understanding of the mechanism by which common risk factors lead to CVD. Completion of the aims will provide a mechanistic explanation for the enhanced risk of cardiovascular ischemia in growing populations with high aldosterone (heart failure, obesity, resistant HTN, low sodium diet) and for the vascular protective effects of MR antagonists. Furthermore, these studies are expected to identify novel treatment targets to prevent cardiovascular ischemia in these rapidly growing and high risk populations.