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

主动脉血管平滑肌细胞在 h 发育过程中的固有硬度

• 批准号: 8822322
• 负责人: Hongyu Qiu
• 金额: $ 43.84万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8822322
• 关键词: Actins; Angiotensins; Animal Model; Animals; Antihypertensive Agents; Aorta; Arteries; Atomic Force Microscopy; Biological Models; Blood Vessels; Canis familiaris; Cardiovascular Diseases; Cells; Complex; Cytoskeleton; Data; Dependence; Development; Elasticity; Endothelial Cells; Extracellular Matrix; Goals; Health; Heart failure; Human; Hypertension; In Vitro; Inbred SHR Rats; Inbred WKY Rats; Investigation; Kidney; Kidney Failure; Lead; Medial; Mediating; Microfilaments; Modeling; Molecular; Peripheral; Pharmacologic Substance; Property; Rattus; Resistance; Rho-associated kinase; Role; Smooth Muscle Myocytes; Smooth Muscle Myosins; Stroke; Techniques; Testing; Tissue Model; Tissues; Vascular resistance; Work; arterial stiffness; inhibitor/antagonist; kinase inhibitor; new therapeutic target; normotensive; novel; novel therapeutic intervention; reconstitution

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.

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，自发性高血压大鼠不仅主动脉血管平滑肌细胞（VSMCs）硬度增加，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的vsmc固有的。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。我们将用复杂的模型系统来验证我们的假设，包括整个动物、分离血管、重组组织和三种不同的高血压动物模型的单细胞观察：首先，在假设1中，我们将采用一种策略来测试内源性VSMC刚度是否有助于高血压的发展。我们将确定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（Specific Aim 1-1）；体外VSMC刚度和动态振荡的变化（Specific Aim 1-2）；VSMC、主动脉VSMC （Specific Aim 1-3）和小阻力动脉（Specific Aim 1-4）收缩状态与僵硬度的相关性；最后，我们将使用选择性平滑肌肌球蛋白抑制剂来确定VSMCs的内在弹性对高血压发展的贡献是否独立于其他因素（Specific Aim 1-5）。其次，在假设2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（Specific Aim 2-1）以及与Rho-激酶相关的潜在调节机制（Specific Aim 2-2）。我们还将阐明rho激酶抑制剂作为高血压治疗的潜在药物靶点之一的机制，直接从VSMC本身的水平（Specific Aim 2-3），这将为主动脉僵硬和高血压的治疗开辟新的途径。