VASCULAR SMOOTH MUSCLE REMODELING--ARGININE VASOPRESSIN

血管平滑肌重塑--精氨酸加压素

• 批准号: 6851011
• 负责人: RAPHAEL A. NEMENOFF
• 金额: $ 36.45万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6851011
• 关键词: JUN kinase; RNA interference; arginine; arginine vasopressin; biological signal transduction; cardiac myocytes; cardiogenesis; cell differentiation; genetic regulation; genetic transcription; growth factor; guanine nucleotide binding protein; immunofluorescence technique; laboratory mouse; laboratory rat; mechanical stress; mitogen activated protein kinase; phenotype; platelet derived growth factor; protein localization; two dimensional gel electrophoresis; vascular smooth muscle

During normal development, vascular smooth muscle cells (VSMC) undergo differentiation from a proliferative phenotype characteristic of neonatal and embryonic vessels, to a contractile phenotype associated with adult vessels. In contrast to development of cardiac or skeletal muscle, VSMC retain much greater plasticity. In adult VSMC, phenotypic modulation resulting in changes in altered expression of a number of muscle-specific genes (SM-markers), results in cells with altered contractile, proliferative and migratory capacity. Transcriptional control of these genes occurs in response to multiple extracellular stimuli including circulating factors, extracellular matrix and mechanical forces. We hypothesize that phenotypic modulation requires sensing by VSMC of these multiple inputs, which integrate at the level of common signal transduction pathways. These pathways act on transcription factors, most critically serum response factor (SRF), that bind to the promoter elements of multple target genes. The goal of this proposal is to define these molecular signaling events and determine how they regulate transcription. During the previous funding period we have demonstrated that coordinated induction of SM-markers by arginine vasopression (AVP) is mediated through activation of the JNK and p38 family of MAP kinases. Induction by mechanical forces also involves these pathways. Conversely, PDGF suppression of SM-gene expression is mediated through activation of Ras and the PI3 kinase/Akt pathways. We have also demonstrated that growth of VSMC on matrices of different composition, through engagement of specific integrins and modulation of cytoskeleton, results in changes in expression of SM-markers. SRF is critical for regulation in all of these settings, and shows altered phosphorylation and subcellular localization. In this application we will focus on understanding the integration of signals generated by vasoconstrictors such as AVP, growth factors, and cell attachment resulting in alterations in gene expression. Three specific aims are proposed. Specific aim 1 will examine the role of MAP kinase and Rho family members in mediating the inductive effects of AVP. The second specific aim will define the mechanisms whereby Ras and Akt cooperate to mediate regulation of SM-gene expression by PDGF and redistribution of SRF. The final specific aim will examine the role of SRF phosphorylation in mediating control of SM-gene expression. These studies should provide a detailed molecular understanding of the events that control phenotypic remodeling in VSMC, and provide potential new targets for controlling this process in disease states.

在正常发育过程中，血管平滑肌细胞(VSMC)经历了从 新生儿和胚胎血管的增殖表型特征，到与成人血管相关的收缩表型。与心肌或骨骼肌的发育相比，VSMC保留了更大的可塑性。在成年VSMC中，表型改变导致一些肌肉特异性基因(SM标记)表达改变，导致细胞收缩、增殖和迁移能力改变。这些基因的转录调控是在多种细胞外刺激下进行的，包括循环因子、细胞外基质和机械力。我们假设表型调制需要VSMC感知这些多个输入，这些输入整合在共同信号转导通路的水平上。这些途径作用于转录因子，最关键的是血清 反应因子(SRF)，与多个靶基因的启动子元件结合。这项提议的目标是定义这些分子信号事件，并确定它们如何调节转录。在之前的资助期间，我们已经证明了精氨酸加压素(AVP)对SM标记物的协同诱导是通过激活JNK和p38家族的MAP激酶来实现的。机械力诱导也涉及到这些途径。相反，PDGF抑制SM-基因的表达是通过激活RAS和PI3激酶/Akt通路来实现的。我们还证明了这种增长 VSMC作用于不同组成的基质，通过与特定整合素的结合和细胞骨架的调控，导致SM-标志物表达的变化。SRF在所有这些环境中都是调节的关键，并显示出磷酸化和亚细胞定位的改变。在这一应用中，我们将重点了解血管收缩因子(如AVP)、生长因子和细胞附着所产生的信号的整合，从而导致基因表达的变化。提出了三个具体目标。具体目标1将 研究MAP激酶和Rho家族成员在AVP诱导效应中的作用。第二个具体目标将确定RAS和Akt协同调节PDGF对SM-基因表达的调节和SRF的重新分布的机制。最终的特定目的将检测SRF磷酸化在介导SM-基因表达调控中的作用。这些研究应该为控制VSMC表型重塑的事件提供详细的分子理解，并为在疾病状态下控制这一过程提供潜在的新靶点。