Smad2 in vascular smooth muscle homeostasis

总结/摘要 血管平滑肌细胞（SMC）表型的畸变导致结构缺陷和机械损伤， 动脉壁的性质，导致动脉僵硬，这与高血压相关，是一种 难治性高血压的独立危险因素。众所周知，动脉壁随着年龄的增长而变硬。在 除高血压外，血管老化也是心血管疾病的独立危险因素， 冠状动脉疾病、中风和心力衰竭。然而，控制血管的因素和机制， 老化，特别是SMC老化和动脉僵硬，在很大程度上仍然是未知的。我们令人兴奋的初步数据 表明Smad 2在维持SMC和血管稳态以及血压中起关键作用。 SMC-组织特异性Smad 2缺陷（Smad 2sm-/-）导致小鼠弹性蛋白和胶原含量的改变 以及血管壁中的结构，导致动脉扩张性降低、脉压增加（指示 动脉僵硬度）和平均动脉压升高。Smad 2 SMC中的血管壁重塑/刚度- 缺陷型小鼠似乎是由SMC过早老化和p53水平升高引起的。实际上 动脉SMC中p53水平的增加沿着Smad 2表达的减少与动脉平滑肌细胞的增龄相关。 老鼠和人类。重要的是，Smad 2的减少与p53的增加也密切相关。 与人类高血压的发病有关。这些数据有力地支持了一个新的假设， Smad 2通过抑制SMC中p53的表达和/或活性来维持血管稳态和血压。 利用原代培养的SMCs，在体内建立Smad 2和p53特异性SMCs敲除小鼠模型， 分子，细胞，组织学和药理学方法，我们将1）测试Smad 2是否是必需的， 维持血管壁弹性和血压稳态; 2）阐明 Smad 2通过抑制p53表达/活性调节SMC稳态;和3）确定是否阻断Smad 2的表达/活性。 p53减弱Smad 2缺陷引起的动脉僵硬和高血压成功完成 本研究将为建立一种新的调节SMC衰老和血压稳态的机制提供理论依据。它将 也使我们能够确定潜在的新方法，可用于开发有效的治疗方法， 衰老或动脉硬化相关的高血压。

Summary/Abstract Aberration of vascular smooth muscle cell (SMC) phenotypes cause structural defects and impaired mechanical properties of artery wall, leading to artery stiffness, which correlates with high blood pressure and is an independent risk factor for the resistant hypertension. It is well-known that arterial wall stiffens with aging. In addition to hypertension, vascular aging is an independent risk factor for cardiovascular diseases including coronary artery disease, stroke and heart failure. However, the factors and mechanisms that control vascular aging, especially SMC aging and artery stiffness, remain largely unknown. Our exciting preliminary data demonstrate that Smad2 plays a critical role in maintaining SMC and vascular homeostasis and blood pressure. SMC-tissue specific deficiency of Smad2 (Smad2sm-/-) in mice causes alterations in elastin and collagen content and structure in the vessel wall, resulting in decreased artery distensibility, increased pulse pressure (indicator of artery stiffness), and increased mean artery pressure. The vascular wall remodeling/stiffness in Smad2 SMC- deficient mice appears to be caused by a premature SMC aging with an elevation in p53 level. In fact, the increase in p53 level along with the decrease in Smad2 expression in artery SMC correlates with the aging in mouse and human. Importantly, the correlation of decreased Smad2 with increased p53 is also closely associated with the onset of hypertension in human. These data strongly support a novel hypothesis that Smad2 maintains vascular homeostasis and blood pressure by inhibiting p53 expression and/or activity in SMC. Using primary culture of SMCs, in vivo Smad2 and p53 SMC-specific knockout mouse models combining with molecular, cellular, histological, and pharmacological approaches, we will 1) test if Smad2 is essential for maintaining the vascular wall elasticity and blood pressure homeostasis; 2) elucidate the mechanism by which Smad2 regulates SMC homeostasis through inhibiting p53 expression/activity; and 3) determine if blockade of p53 attenuates Smad2 deficiency-caused artery stiffness and hypertension. Successful completion of the proposed study will establish a novel mechanism regulating SMC aging and blood pressure homeostasis. It will also allow us to identify potential novel approaches that may be used to develop effective therapeutics for treating aging or artery stiffness-related hypertension.