VASCULAR SMOOTH MUSCL ADRENOCEPTOR FUNCTION & EXPRESSION

我们最近发现，多达4种不同的α-肾上腺素受体（AR） 亚型可由血管平滑肌细胞（SMC）表达， 动脉和静脉之间的一系列亚型不同， 条件可以诱导正常抑制亚型的表达。 小 关于这些不同的α AR的表达的调节是已知的 SMC的。 此外，存在的所有亚型可能都不介导 收缩和其他SMC功能不清楚。 虽然升高 儿茶酚胺活性促进SMC生长&是一个危险因素 动脉粥样硬化和高血压性肥大 α AR调节SMC生长和所涉及的α AR亚型。 的 待检验的假设是：（1）特定的α AR亚型 调节SMC的生长和收缩和结构蛋白的表达， 从而将交感神经状态与SMC生长和分化联系起来。 （二） 血管壁微环境中的基本信号， 儿茶酚胺、氧和压力诱导的细胞拉伸调节 特异性α AR亚型的表达。 以下目标将是 在大鼠主动脉平滑肌细胞的细胞培养和血管中原位检测 墙 目的1检查刺激不同α AR的作用， 亚型对生长和基因表达（mRNA和蛋白质）的α和 β-肌动蛋白 目的2确定各亚型刺激的影响 对同源和其它α AR亚型的表达的影响。 目标3调查 通过氧调节α AR表达。 目标4考察了 细胞拉伸（压力）对α AR表达的影响。 目标5确定 涉及基因转录速率（核径流）、mRNA 稳定性，以及DNA和蛋白质合成的改变表达， 肌动蛋白、α AR亚型和α AR刺激诱导的SMC生长， 组织氧和细胞伸展。 目的6测试假设O/2- α 1B-AR基因中的结合血红素蛋白和序列介导缺氧 刺激alpha 1B表达。 这些研究将有助于了解 一个令人困惑的基本问题，即为什么SMC表达多个 alphaAR亚型以及亚型的表达是如何调节的。 的 研究结果可以为研究和理解 血管肥大性疾病，建立联系， 儿茶酚胺、缺血、血压和特异性 调节SMC生长的α AR亚型。 此外，这些研究 将确定血管内压力和组织氧如何影响 表达的α-肾上腺素能受体亚型的模式和密度 血管平滑肌

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.