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: 8458343
• 负责人: Hongyu Qiu
• 金额: $ 5.89万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8458343
• 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; DNA Sequence Rearrangement; 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; inhibitor/antagonist; kinase inhibitor; new therapeutic target; normotensive; novel; novel therapeutic intervention; public health relevance; 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，人们对其机制知之甚少。大多数先前的工作都集中在细胞外基质或内皮控制上。我们的初步数据显示，与血压正常的 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 (VSMC) 硬度增加，而且弹性振荡也发生变化。该提议的中心假设是，高血压引起的大动脉僵硬度增加的一个重要组成部分也是孤立的 VSMC 所固有的。该提案的目标是确定高血压中孤立的 VSMC 硬度增加，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。我们将通过复杂的模型系统来测试我们在本提案中的假设，包括整个动物、离体血管、重建组织以及通过以下策略对三种不同的高血压动物模型进行的单细胞观察：首先，在假设1中，我们将采用一种策略来测试内在的VSMC硬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（具体目标 1-1）；体外 VSMC 硬度和动态振荡的变化（具体目标 1-2）； VSMC 和主动脉 VSMC（具体目标 1-3）和小阻力动脉（具体目标 1-4）的收缩状态与硬度之间的相关性；最后，我们将使用选择性平滑肌肌球蛋白抑制剂来确定 VSMC 的内在弹性对高血压发展的贡献是否独立于其他因素（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主动脉VSMC硬度改变所涉及的细胞/分子机制（具体目标2-1）以及与Rho激酶相关的潜在调节机制（具体目标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途径。