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Network signature of low-flow endothelial dysfunction

低流量内皮功能障碍的网络特征

基本信息

批准号：
10666476
负责人：
MARK STEPHEN TAYLOR
金额：
$ 38.5万
依托单位：
UNIVERSITY OF SOUTH ALABAMA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10666476
关键词：
Abate Arteries Atherosclerosis Blood Vessels Blood flow Calcium-Activated Potassium Channel Cardiovascular Diseases Cardiovascular system Carotid Arteries Cell membrane Cessation of life Chronic Chronic Disease Clinical Complex Coupling Data Development Distal Endoplasmic Reticulum Endothelial Cells Endothelium Event Exhibits Feedback Fire - disasters Frequencies G-Protein-Coupled Receptors Genetic Hemostatic function Homeostasis Human Hypertension ITPR1 gene Image Impairment Inflammation Inositol Intervention Island Knockout Mice Lead Ligation Liquid substance Modeling Molecular Mus Obstruction Pathologic Pathology Patients Pattern Peripheral Peripheral arterial disease Permeability Phenotype Physiological Play Potassium Channel Role Signal Transduction Specificity Structure TRP channel Time Tunica Intima Vascular Diseases Vascular remodeling Vasodilation confocal imaging endothelial dysfunction extracellular functional loss inorganic phosphate mouse model novel novel therapeutics preservation prevent receptor response shear stress therapeutic target vasoconstriction

项目摘要

PROJECT SUMMARY/ABSTRACT The endothelium is a crucial regulator of vascular homeostasis and endothelial dysfunction is a hallmark of cardiovascular disease. The challenge in searching for new therapies is finding early control points that prevent the shift to broad pathologic signaling profiles and disrupt the endothelial network. Employing novel imaging and analysis approaches, we have identified discrete patterns of dynamic Ca2+ signalling along the vascular intima that underlie vascular function and direct the specificity, sensitivity and intensity of prevailing vascular responses. These patterns, defined by profiles of dynamic event parameters (frequency, amplitude, duration and spatial spread), form distinct signatures along the endothelial network. The complex spectrum of endothelial Ca2+ events (from isolated brief transients to broad multicellular waves) result from positive feedback interaction between plasma membrane TRP channels (Ca2+ entry) and endoplasmic reticulum IP3Rs (Ca2+ release). Small conductance Ca2+-activated K+ channels (KCa) play a key role in this signaling by exerting Ca2+-dependent hyperpolarization and amplifying Ca2+ influx through TRP channels (particularly fluid shear stress (FSS)- activated TRPV4 channels). In flow-deprived distal arteries from patients with peripheral artery disease, the endothelium exhibits a distinctive truncated Ca2+ signature characterized by spatially restricted small amplitude transients. This anomalous Ca2+ profile appears early in a low-flow carotid ligation mouse model, giving rise to endothelial dysfunction and vascular remodelling. These low-flow adaptations involve progressive loss of endothelial KCa2.3 channels and suggest an early loss of cooperative KCa/TRPV4 action. We hypothesize that disruption of TRPV4-KCa2.3 signaling under conditions of low FSS causes a progressive, highly restricted endothelial Ca2+ signature that promotes endothelial dysfunction and vascular remodeling. Aim 1 will characterize the role of TRPV4-KCa2.3 signaling in physiologic Ca2+ signatures along the arterial endothelium. We will conduct confocal imaging (with novel high-content analysis) and employ endothelium- specific knockout mice (ecKCa2.3-/- and ecTRPV4-/-) as well as human peripheral arteries to elucidate cooperative channel impacts under differential FSS. Aim 2 will determine whether low/oscillatory FSS causes truncation of the TRPV4-KCa2.3-dependent endothelial Ca2+ signature that leads to endothelial dysfunction and vascular remodeling. We will employ a partial ligation mouse model to assess the magnitude and time course of TRPV4- KCa2.3-specific impacts on Ca2+ signaling, vasoreactivity and vascular wall thickening. Aim 3 will determine whether preservation of endothelial TRPV4-KCa2.3 Ca2+ signaling ameliorates development of functional and structural vascular changes resulting from chronic low flow. We will also assess whether interventions to preserve the Ca2+ signature directly abate pathologic impacts of low flow.

项目总结/文摘