Intrinsic Stiffness of Aortic Vascular Smooth Muscle Cell In The Development of h

描述（由申请人提供）：血管僵硬度增加是高血压的基本组成部分，然而，对其机制知之甚少。大多数先前的工作集中在细胞外基质或内皮控制。我们的初步数据显示，不仅主动脉血管平滑肌细胞（VSMCs）的刚度增加，但也在自发性高血压大鼠的弹性变化的振荡相比，血压正常的Wistar-Kyoto（WKY）大鼠。该建议的中心假设是，高血压中大动脉硬度增加的重要组成部分也是孤立的VSMC固有的。该提案的目标是确定高血压中孤立的VSMC刚度增加，并确定介导这些变化的潜在细胞/分子机制，然后对其进行研究以发现高血压的新治疗方法。我们将测试我们的假设在这个建议与复杂的模型系统，包括整个动物，离体血管，重组组织和单细胞观察与三种不同的高血压动物模型通过以下策略：首先，在假设1，我们将纳入一个策略，以测试是否固有的VSMC刚度有助于高血压的发展。我们将确定外周血管阻力增加和主动脉血管僵硬度增加之间的相关性（具体目标1-1）;体外VSMC刚度和动态振荡的改变（具体目标1-2）; VSMC和主动脉VSMC的收缩状态和刚度之间的相关性（特定目标1-3）和小阻力动脉（具体目标1-4）;最后，我们将使用选择性平滑肌肌球蛋白抑制剂来确定VSMC的内在弹性是否对VSMC的发育有贡献。高血压与其他因素无关（具体目标1-5）。其次，在假设2中，我们将研究高血压发展过程中参与主动脉VSMC刚度改变的细胞/分子机制（特异性目的2-1）和与Rho激酶相关的潜在调节机制（特异性目的2-2）。我们还将阐明Rho激酶抑制剂作为针对VSMC本身水平的高血压治疗的潜在药物靶点之一的机制（具体目标2-3），这为治疗主动脉僵硬和高血压开辟了新的途径。

DESCRIPTION (provided by applicant): An increase in vascular stiffness is a fundamental component of hypertension, however, little is known about mechanisms. Most prior work has focused on the extracellular matrix or endothelial control. Our Preliminary Data revealed not only that aortic vascular smooth muscle cells (VSMCs) stiffness increases but also that the oscillation of elasticity changes in spontaneously hypertensive rats compared to normotensive Wistar-Kyoto (WKY) rats. The central hypothesis of this proposal is that a significant component of the increased large artery stiffness in hypertension also is intrinsic to isolated VSMCs. The goal of this proposal is to establish that isolated VSMC stiffness increases in hypertension and to determine potential cellular/molecular mechanisms mediating these changes, which could then be investigated to uncover novel therapeutic approaches for hypertension. We will test our Hypothesis in this proposal with complex model systems that includes whole animal, isolated vessel, reconstituted tissue and the single cell observations with three different hypertensive animal models by the following strategies: First, in Hypothesis 1, we will incorporate a strategy to test whether intrinsic VSMC stiffness contributes to the development of hypertension. We will determine the correlation between increased peripheral vascular resistance and increased aortic vascular stiffness (Specific Aim 1-1); the alterations of VSMC stiffness and dynamic oscillation in vitro (Specific Aim 1-2); the correlation between contractile status and stiffness o VSMC and aortic VSMC (Specific Aim 1-3)and small resistance arteries(Specific Aim 1-4); finally we will use a selective smooth muscle myosin inhibitor to determine whether the contribution of intrinsic elasticity of VSMCs to the development of hypertension is independent from other factors (Specific Aim 1-5). Secondly, in Hypothesis 2, we will investigate the cellular/molecular mechanisms involved in the alteration of aortic VSMC stiffness in the development of hypertension (Specific Aim 2-1) and the potential regulative mechanism related to the Rho- kinase (Specific Aim 2-2). We will also elucidate the mechanism of Rho-kinase inhibitor as one of potential pharmaceutical targets of hypertension therapy directed at the level of the VSMC itself (Specific Aim 2-3), which open up new avenues for therapy of aortic stiffness and hypertension.