VASCULAR SMOOTH MUSCLE REMODELING--ARGININE VASOPRESSIN

血管平滑肌重塑--精氨酸加压素

• 批准号: 7098764
• 负责人: RAPHAEL A. NEMENOFF
• 金额: $ 37.54万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7098764
• 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）经历从血管平滑肌细胞（VSMC）分化为血管平滑肌细胞（VSMC）。 从新生儿和胚胎血管特有的增殖表型到与成人血管相关的收缩表型。与心肌或骨骼肌的发育相反，VSMC保留了更大的可塑性。在成人VSMC中，表型调节导致许多肌肉特异性基因（SM标记物）表达改变，导致细胞收缩、增殖和迁移能力改变。这些基因的转录控制响应于多种细胞外刺激而发生，所述细胞外刺激包括循环因子、细胞外基质和机械力。我们假设，表型调制需要通过VSMC的这些多个输入，在共同的信号转导通路的水平整合传感。这些途径作用于转录因子，最关键的是血清 反应因子（SRF），其与多个靶基因的启动子元件结合。这个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标记物的协调诱导是通过激活JNK和MAP激酶的p38家族介导的。机械力的诱导也涉及这些途径。相反，PDGF对SM基因表达的抑制是通过Ras和PI 3激酶/Akt途径的激活介导的。我们也证明了增长 在不同组成的基质上的VSMC，通过特定整合素的参与和细胞骨架的调节，导致SM标记物表达的变化。SRF在所有这些环境中对调节至关重要，并显示出改变的磷酸化和亚细胞定位。在这个应用程序中，我们将集中在了解血管收缩剂，如AVP，生长因子和细胞附着导致基因表达的改变所产生的信号的整合。提出了三个具体目标。具体目标1将 研究MAP激酶和Rho家族成员在介导AVP诱导效应中的作用。第二个具体目标将定义Ras和Akt合作介导PDGF调节SM基因表达和SRF再分布的机制。最后的具体目标将检查SRF磷酸化在介导控制SM基因表达中的作用。这些研究应该提供一个详细的分子理解的事件，控制VSMC的表型重塑，并提供潜在的新目标，控制这一过程中的疾病状态。