Intrinsic stiffness of aortic vascular smooth muscle cell in the development of h

描述（由申请人提供）：血管僵硬度的增加是高血压的基本组成部分，然而，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上。我们的初步数据显示，与正常的Wistar- Kyoto （WKY）大鼠相比，自发性高血压大鼠（SHR）不仅主动脉血管平滑肌细胞（VSMC）刚度增加，而且弹性振荡也发生了变化。该建议的中心假设是高血压患者大动脉僵硬度增加的一个重要组成部分也是孤立性VSMC的内在因素。本研究的目的是确定高血压患者分离的VSMC硬度增加，并确定介导这些变化的潜在细胞/分子机制，从而研究高血压的新治疗方法。我们将通过以下策略来验证我们在本提案中的假设：首先，在Specific Aim 1-1中，我们将确定SHR患者全身性高血压发展过程中外周血管阻力增加与主动脉血管僵硬度增加之间的相关性；其次，在Specific Aim 1-2中，我们将确定SHR患者高血压发展过程中体外VSMC刚度和动态振荡的变化；第三，在Specific Aim 2-1中，我们将研究高血压发生过程中主动脉VSMC硬度改变的细胞/分子机制。最后，在Specific Aim 2-2中，我们将从VSMC本身的水平阐明高血压治疗的潜在药物靶点的机制。一个具体的目标，将在本提案中进行研究，是抑制Rho激酶，这已经被提议用于高血压治疗。

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 cell (VSMC) stiffness increases but also that the oscillation of elasticity changed in spontaneously hypertensive rats (SHR) 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 VSMC's. 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 by the following strategies: First, in Specific Aim 1-1, we will determine the correlation between increased peripheral vascular resistance and increased aortic vascular stiffness during the development of systemic hypertension in SHR; Second, in Specific Aim 1-2, we will determine the alterations of VSMC stiffness and dynamic oscillation in vitro during the development of hypertension in SHR; Third, in Specific Aim 2-1, we will investigate the cellular/molecular mechanisms involved in the alteration of aortic VSMC stiffness in the development of hypertension. Finally, in Specific Aim 2-2, we will elucidate the mechanism of potential pharmaceutical targets of hypertension therapy directed at the level of the VSMC itself. One specific target, which will be studied in thi proposal, is inhibition of Rho kinase, which has already been proposed for hypertension therapy.