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: 8714326
• 负责人: Hongyu Qiu
• 金额: $ 34.79万
• 依托单位: RBHS-NEW JERSEY 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 2013-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8714326
• 关键词: Adhesives; Animal Model; Antihypertensive Agents; Aorta; Arteries; Atomic Force Microscopy; Blood Vessels; Cardiovascular Diseases; Cells; Cytoskeleton; DNA Sequence Rearrangement; Data; Development; Elasticity; Extracellular Matrix; Goals; Health; Heart failure; Human; Hypertension; In Vitro; Inbred SHR Rats; Inbred WKY Rats; Investigation; Kidney Failure; Lead; Medial; Mediating; Microfilaments; Molecular; Peripheral; Peripheral Resistance; Pharmacologic Substance; Proteins; Rattus; Rho-associated kinase; Role; Smooth Muscle Myocytes; Stroke; Techniques; Testing; Tissue Model; Tissues; Vascular resistance; Work; age effect; constriction; in vivo; middle age; 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 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.

描述（由申请人提供）：血管刚度的增加是高血压的基本组成部分，但是，对机制知之甚少。大多数先前的工作都集中在细胞外基质或内皮控制上。我们的初步数据不仅表明，与正常性的Wistar-Kyoto（WKY）大鼠相比，自发性高血压大鼠（SHR）的弹性振荡的僵硬增加，而且弹性的振荡也会增加。该提议的中心假设是高血压大动脉刚度的重要组成部分也是孤立的VSMC的固有的。该提案的目的是确定孤立的VSMC刚度增加了高血压的增加，并确定介导这些变化的潜在细胞/分子机制，然后可以研究这些变化以发现新型的高血压治疗方法。我们将通过以下策略在该提案中检验我们的假设：首先，在特定的目标1-1中，我们将在SHR系统性高血压发展过程中确定增加的周围血管抗性与主动脉血管僵硬增加之间的相关性；其次，在特定的目标1-2中，我们将在SHR中高血压发展过程中确定VSMC刚度和动态振荡的改变。第三，在特定目标2-1中，我们将研究与主动脉VSMC刚度改变在高血压发展中有关的细胞/分子机制。最后，在特定目标2-2中，我们将阐明针对VSMC本身水平的高血压治疗的潜在药物靶标的机理。将在提案中研究的一个特定靶标是对Rho激酶的抑制作用，Rho激酶已经提出了用于高血压疗法的。