Mechanism of Resistance Artery Contraction

动脉收缩阻力机制

• 批准号: 6621656
• 负责人: JOSEPH ELLIOTT BRAYDEN
• 金额: $ 34.09万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6621656
• 关键词: antisense nucleic acid; biological signal transduction; calcium channel; calcium flux; cell morphology; cerebral artery; cerebrovascular system; confocal scanning microscopy; fluorescent dye /probe; laboratory rat; membrane potentials; phospholipase C; protein tyrosine kinase; tissue /cell culture; vascular resistance; vascular smooth muscle; vasoconstriction; voltage /patch clamp; voltage gated channel

Pressure-induced (myogenic) tone is a physiological response centrally involved in autoregulation of blood flow in the brain. A fundamental mechanism involved in the regulation of cerebral artery constriction is depolarization of the smooth muscle cell membrane and increased Ca2+ entry. We have recently identified a cerebrovascular cation channel that could play a major role in both the depolarization and Ca2+-entry processes. Additional preliminary data indicate that this cation channel may be a member of the mammalian transient receptor potential (Trp) family. In the proposed studies, we will characterized the properties of these channels and determine their functional roles in the cerebral circulation. Specific Aim 1. To elucidate the biophysical and pharmacological properties of cation channels activated by cell swelling or increased pressure in cerebrovascular smooth muscle cells and the signal transduction pathways involved in their regulation. These experiments will provide evidence that will establish the role of these channels in pressure-induced depolarization of cerebral artery myocytes. Specific Aim 2. To establish the presence and functional roles of Trp channels in cerebral artery smooth muscle cells. This aim will determine which of the Trp channels are present in cerebrovascular muscle cells and what physiological roles they serve in cerebral resistance arteries. These studies will be performed using a unique combination of approaches from molecular to whole tissue levels to provide an integrated picture of cerebral artery contractile mechanisms involving membrane potential and regulation of [Ca2+]i. State-of-the-art techniques will be employed including membranes potential, cell Ca2+, and diameter measurements in intact arteries, ion channel and cell Ca2+, measurements in freshly isolated vascular smooth muscle cells, and anti- sense oligodeoxynucleotide strategies to suppress Trp channel function. The proposed studies should significantly advance our understanding of the role of cationic channels in the regulation of vascular tone in the brain and indicate novel targets for agents that could be used to correct pathological alterations in cerebral blood flow.

压力引起的（肌源性）张力是一种主要参与大脑血流自动调节的生理反应。调节脑动脉收缩的一个基本机制是平滑肌细胞膜的去极化和增加 Ca2+ 的进入。我们最近发现了一种脑血管阳离子通道，它可以在去极化和 Ca2+ 进入过程中发挥重要作用。其他初步数据表明，该阳离子通道可能是哺乳动物瞬时受体电位 (Trp) 家族的成员。在拟议的研究中，我们将表征这些通道的特性并确定它们在脑循环中的功能作用。具体目的 1. 阐明脑血管平滑肌细胞中细胞肿胀或压力升高激活的阳离子通道的生物物理和药理学特性以及参与其调节的信号转导途径。这些实验将提供证据来确定这些通道在压力诱导的脑动脉肌细胞去极化中的作用。具体目标 2. 确定脑动脉平滑肌细胞中 Trp 通道的存在及其功能作用。这一目标将确定哪些色氨酸通道存在于脑血管肌细胞中以及它们在脑阻力动脉中发挥什么生理作用。这些研究将使用从分子水平到整个组织水平的独特方法组合来进行，以提供涉及膜电位和 [Ca2+]i 调节的脑动脉收缩机制的综合图景。将采用最先进的技术，包括完整动脉的膜电位、细胞 Ca2+ 和直径测量、离子通道和细胞 Ca2+、新鲜分离的血管平滑肌细胞的测量以及抑制 Trp 通道功能的反义寡脱氧核苷酸策略。拟议的研究将显着增进我们对阳离子通道在大脑血管张力调节中的作用的理解，并为可用于纠正脑血流病理改变的药物指明新的靶标。