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

 描述(申请人提供)：醛固酮激活肾脏中的盐皮质激素受体(MR)，以调节钠的处理和血压(BP)。醛固酮升高在包括顽固性高血压、肥胖症和心力衰竭在内的不断增长的人群中很常见，并预测这些患者发生心肌梗死(MI)、中风和死亡的风险。MR拮抗剂防止这些结果与血压变化不成比例，从而导致该计划的总体假设：血管MR直接促进血管功能和心血管疾病(CVD)，识别由血管MR控制的基因和途径将确定CVD的新机制和治疗靶点。我们发现功能性MRS存在于人血管平滑肌细胞(SMC)和内皮细胞(EC)中。在最初的5年里，我们专注于SMC-MR，我们的发现，包括一种新的血管重塑机制和SMC-MR在随年龄增长的血压调节中的直接作用，极大地改变了我们对MR生物学和心血管疾病机制的研究范式。在接下来的4年里，我们建议探讨EC-MR在心血管疾病中的有争议的作用。为此，我们建立了一种创新的小鼠模型，其MR特定地从内皮细胞(而不是白细胞)中删除，并发现EC-MR缺失可以防止肥胖和高脂血症导致的内皮功能障碍。我们建议使用这只EC-MR-KO小鼠来检验这一新的假设，即EC-MR在肥胖、高血压和高脂血症等心脏危险因素存在的情况下，特别是在内皮功能障碍、血管炎症和动脉粥样硬化进展的发展中起作用。我们提出了三个目标：1)利用EC-MR-KO和MR正常小鼠的肠系膜血管丝肌图，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)探讨EC-MR增强血管炎症的机制。使用体外平行平板流动室内试验，我们发现EC-MR增强了T细胞在ECs中的黏附和迁移，我们建议使用流式细胞仪和活体显微镜来研究其在体外和体内的机制；以及3)使用EC-MR-KO小鼠和易发生动脉粥样硬化的ApoE-KO小鼠杂交，研究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促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(心力衰竭、肥胖症、抵抗性HTN、低钠饮食)日益增长的人群中心血管缺血风险增加以及血管保护作用提供一个机制解释。 敌手先生。此外，这些研究有望确定新的治疗目标，以预防这些快速增长的高危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.