VASCULAR SMOOTH MUSCL ADRENOCEPTOR FUNCTION & EXPRESSION

血管平滑肌肾上腺素受体功能

• 批准号: 2230085
• 负责人: JAMES E FABER
• 金额: $ 20.59万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-05 至 1998-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2230085
• 关键词: actins; alpha adrenergic receptor; binding proteins; catecholamines; cytoskeleton; genetic promoter element; genetic regulation; genetic transcription; growth /development; heme; laboratory rat; messenger RNA; nuclear runoff assay; receptor expression; sarcomeres; tissue /cell culture; vascular smooth muscle

We have recently found that up to 4 different alpha-adrenoceptor (AR) subtypes may be expressed by vascular smooth muscle cells (SMCs), that the array of subtypes differs between artery and vein, and that certain conditions may induce expression of a normally repressed subtype. Little is known concerning regulation of expression of these different alphaARs by SMCs. Moreover, all of the subtypes present may not mediate contraction & their other SMC functions are unclear. While elevated catecholamine activity promotes SMC growth & is a risk factor for atherosclerosis & hypertensive hypertrophy little is known about how alphaARs regulate SMC growth and the alphaAR subtypes involved. The hypotheses to be tested are that: (1) A specific alphaAR subtype(s) modulates SMC growth and expression of contractile & structural proteins, thereby linking sympathetic state to SMC growth & differentiation. (2) Fundamental signals in the vascular wall microenvironment, ie., catecholamines, oxygen and pressure-induced cell stretch regulate expression of specific alphaAR subtypes. The following aims will be examined in rat aorta SMCs in cell culture and in situ in the vascular wall. Aim 1 examines the effect of stimulation of different alphaAR subtypes on growth and gene expression (mRNA & protein) of alpha- and beta-actin. Aim 2 determines the influence of stimulation of each subtype on expression of the cognate & other alphaAR subtypes. Aim 3 investigates regulation of alphaAR expression by oxygen. Aim 4 examines the effect of cell stretch (pressure) on alphaAR expression. Aim 5 determines involvement of changes in gene transcription rate (nuclear runoff), mRNA stability, and DNA & protein synthesis in the altered expression of actins, alphaAR subtypes and SMC growth induced by alphaAR stimulation, tissue oxygen and cell stretch. Aim 6 tests the hypothesis that an O/2- binding heme protein & sequences in the alpha1B-AR gene mediate hypoxia stimulation of alpha1B expression. These studies will yield insight into a perplexing fundamental question, namely why SMCs express multiple alphaAR subtypes and how expression of the subtypes is regulated. The findings could open up new opportunities in the study and understanding of vascular hypertrophic diseases by establishing linkage among catecholamines, ischemia, blood pressure and expression of specific alphaAR subtypes that modulate SMC growth. In addition, these studies will identify how intravascular pressure and tissue oxygen influence the pattern and density of alpha-adrenergic receptor subtypes expressed by vascular smooth muscle.

我们最近发现多达4种不同的α-肾上腺素能受体(AR) 亚型可能由血管平滑肌细胞(SMCs)表达，即 动脉和静脉的亚型排列不同，而且一定 条件可以诱导正常抑制亚型的表达。一点儿 已知关于这些不同的字母受体表达的调节 由SMCS提供。此外，存在的所有亚型可能都不会起到中介作用 收缩&它们的其他SMC功能尚不清楚。在提升的同时 儿茶酚胺活动促进SMC生长，是 动脉粥样硬化和高血压肥厚的机制目前知之甚少。 α受体调节SMC的生长和所涉及的αAR亚型。这个 有待检验的假设是：(1)一个特定的AlphaAR亚型(S) 调节SMC的生长和收缩及结构蛋白的表达， 从而将交感状态与SMC的生长和分化联系起来。(2) 血管壁微环境中的基本信号，即 儿茶酚胺、氧气和压力诱导的细胞拉伸调节 特定字母AR亚型的表达。以下目标将是 大鼠主动脉平滑肌细胞的细胞培养和血管内原位检测 墙。目的1考察不同α-AR刺激的效果 α-和α-亚型对生长和基因表达(mRNA和蛋白质)的影响 β-肌动蛋白。目标2确定各亚型刺激的影响 关于同源词和其他字母AR亚型的表达。AIM 3调查 氧对α-AR表达的调节作用。目标4考察了以下因素的影响 细胞拉伸(压力)对αAR表达的影响。目标5确定 参与基因转录速率(核径流)、mRNA的变化 在改变的表达中的稳定性和DNA和蛋白质合成 肌动蛋白、αAR亚型与αAR刺激诱导的SMC生长 组织氧气和细胞伸展。AIM 6测试了O/2- α1B-AR基因中的结合血红素蛋白和序列介导缺氧 刺激Alpha1B的表达。这些研究将产生对 一个令人困惑的基本问题，即为什么SMC表达多个 AlphaAR亚型以及亚型表达的调控方式。这个 这些发现可能会为研究和理解 血管肥厚性疾病之间建立联系 儿茶酚胺与脑缺血、血压及特异性表达 调节SMC生长的AlphaAR亚型。此外，这些研究 将确定血管内压和组织氧是如何影响 α-肾上腺素能受体亚型表达的模式和密度 血管平滑肌。