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Mechanisms of resistance artery contraction

阻力动脉收缩的机制

基本信息

批准号：
7342811
负责人：
JOSEPH ELLIOTT BRAYDEN
金额：
$ 36.9万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-04-01 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7342811
关键词：
Agonist Animals Antisense Oligonucleotides Arteries Arts Behavior Blood Vessels Blood capillaries Blood flow Brain Calcium Calcium Channel Caliber Cardiovascular system Cations Cell membrane Cells Cerebrospinal Fluid Cerebrovascular Circulation Cerebrum Communication Coupling Data Dilator Endothelial Cells Endothelium Endothelium-Dependent Relaxing Factors Event Family Fingerprint Gene Silencing Homeostasis Hormonal In Vitro Ion Channel Knockout Mice L-Type Calcium Channels Life Link Localized Measurement Mechanics Mediating Mediator of activation protein Membrane Membrane Potentials Methodology Modeling Molecular Monovalent Cations Muscle Cells Nature Normal tissue morphology Numbers Pathway interactions Perfusion Physiological Play Positioning Attribute Potassium Property Protein Kinase C Range Receptor Activation Regulation Research Personnel Resistance Role Signal Transduction Smooth Muscle Smooth Muscle Myocytes System TRPC3 ion channel TRPV channel Techniques Tissues Translating Vascular Endothelial Cell Vascular Smooth Muscle Vasoconstrictor Agents Vasodilation Vasodilator Agents Vasomotor Work arteriole base blood flow measurement brain circulation cGMP-dependent protein kinase Ibeta capillary capsaicin receptor cerebral artery cerebrovascular concept expression cloning in vivo knowledge base large-conductance calcium-activated potassium channels member mouse Smc1l1 protein mouse Smc1l2 protein novel pressure programs protein expression receptor relating to nervous system research study resistance mechanism response vasoconstriction

项目摘要

The major objective of this proposal is to elucidate the functional significance of several novel mediators and mechanisms involved in regulating intracellular Ca2+ and contractility of cerebral arteries. Through their constrictor and dilator activity, cerebral arteries tightly regulate blood flow and capillary perfusion pressure within a range that sustains normal brain function. We have discovered that members of the transient receptor potential (TRP) superfamily of ion channels are present in cerebral arteries and that these channels play novel, specific and diverse roles in cerebrovascular function: TRPM4 subserves mechanotransduction.. (Aim 1); TRPC3 transduces vasoconstrictor receptor responses (Aim 2); TRPV4 has a unique role in endothelial/smooth muscle communication (Aim 3). We propose to elucidate the properties of these different TRP channels in the cerebral vasculature, and determine their vasoregulatory roles. Specific Aim 1: To define the properties, signal coupling mechanisms, and unique functional roles of TRPM4 channels in cerebral arteries. These experiments will reveal the biophysical properties of TRPM4 channels in native vascular smooth muscle, determine their possible mechanosensitive nature, and consider their in vivo functionality. Specific Aim 2: To elucidate the roles and regulation of nativeTRPCSchannels in agonist induced Ca2+ influx and cerebral vasoconstriction. These experiments will demonstrate the possible role of TRPC3 channels as receptor-operated cation channels in vascular smooth muscle and elucidate the mechanisms by which vascular TRPC3 activity is controlled. Specific Aim 3: To define and differentiate the roles of TRPV4 channels in cerebral arteries. Our preliminary data suggest a novel and unexpected role for TRPV4 channels in endothelium-dependent vasodilator activity, involving endothelium-derived hyyperpolarizing factors, TRPV4 channels, and local Ca2+ release events (Ca2+ sparks). In Aim 3 we will reveal the specific mechanisms involved in these responses. The use of multiple, state-of-the-art techniques (membrane potential, cell Ca2+, diameter, ion channel recording, in vivo blood flow measurements, gene silencing) and a unique combination of approaches from the molecular to the whole animal will provide a comprehensive view of the role of TRP channels in the cerebral circulation and indicate novel targets for agents that could be used to correct pathological alterations in cerebral blood flow.

本提案的主要目的是阐明几种新型介质的功能意义