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eN0S/TSP2

基本信息

批准号：
8250616
负责人：
William C Sessa
金额：
$ 47.7万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8250616
关键词：
Age Angiogenesis Inhibitors Biomechanics Blood flow Breeding Cell physiology Complement Data Disease Endothelial Cells Exhibits Feedback Fibroblast Growth Factor 2 Focal Adhesions Gene Expression Healed Homologous Gene Impairment In Vitro Instruction Ischemia Knock-in Mouse Knock-out Knockout Mice Laboratories Lead Limb structure Link Liquid substance MAP Kinase Gene MMP2 gene Maps Mediating Molecular Mus Pathway interactions Patients Peripheral arterial disease Phenotype Process Production Property Proteins Recovery Regulation Reporting Role Signal Transduction Stimulation of Cell Proliferation THBS2 gene Testing Thrombospondin 1 Time Tissues Tube Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors Vascular remodeling Wound Healing angiogenesis defined contribution extracellular healing human NOS3 protein in vivo migration mutant novel therapeutics research study response shear stress stress activated protein kinase thrombospondin 2 tissue repair

项目摘要

PROJECT SUMMARY (See instructions): The relationship between thrombospondin 2 (TSP2) and endothelial nitric oxide synthase (eNOS) are not known. Activation of VEGFR-2 via VEGF or by fluid shear stress activates the protein kinase Akt and the endothelial specific Akt substrate, endothelial nitric oxide synthase (eNOS), leading to arteriogenesis and angiogenesis. As inferred from exciting preliminary studies from our laboratories, TSP2 serves as a negative regulator of the Akt-1/eNOS pathway. Previously, we have reported that TSP2 knockout mice (TSP2-K0) demonstrate enhanced arteriogenesis and blood flow recovery in response to limb ischemia and augmented tissue healing. Interestingly, our preliminary studies show that TSP2 levels are elevated in eNOS-KO and Akt1-KO mice, which both display marked impairments in arteriogenesis and angiogenesis and NO, per se, negatively regulates TSP2 levels. Moreover, TSP2/eN0S double knockout (DKO) mice exhibit substantial improvements in blood flow recovery and tissue repair. Thus, we hypothesize that regulation of TSP2 expression by eNOS-derived NO constitutes a previously undefined pro-arteriogenic and pro-angiogenic property of NO. To test this idea, we will: 1. test the hypothesis that the Akt1/eNOS axis mediates arteriogenic and angiogenic responses in vivo, in part, by repressing TSP2 levels; 2. determine the mechanism(s) through which the Akt1/eNOS axis and crosstalk with ERK regulates TSP2 and arteriogenesis; and 3. dissect the regulation of the N0/TSP2 pathway and other endothelial cell functions during in vitro angiogenesis. Collectively, these experiments will allow us to delve deeply into the functional antagonism of arteriogenesis and angiogenesis by TSP2, and to delineate how NO regulates TSP2 gene expression and blood flow recovery after limb ischemia.

项目概述（见说明）：