Arterial Vasoregulation by Notch Signaling

通过 Notch 信号调节动脉血管

基本信息

批准号：
10209195
负责人：
AARON PROWELLER
金额：
$ 52.33万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
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：
2021-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10209195
关键词：
Acute Adult Animal Disease Models Animals Arteries Biological Assay Blood Pressure Blood Vessels Blood flow Cell Communication Cell Compartmentation Chronic Clinical Coupled DNA Sequence Alteration Development Dilator Disease Endothelial Cells Endothelium Enzymes Equilibrium Exhibits Foundations Functional disorder Gene Expression Generations Goals Health Human Hypertension Hypotension Impairment In Vitro Instruction Knowledge Laboratories Left Ligands Measures Mediating Molecular Molecular Profiling Morbidity - disease rate Mus Muscle function Myography Myosin ATPase Myosin Light Chain Kinase Myosin Light Chains Pathway interactions Peripheral Pharmacology Phenotype Phosphorylation Phosphotransferases Physiologic intraventricular pressure Physiological Physiology Post-Translational Protein Processing Production Protein Dephosphorylation Regulation Relaxation Resistance Role Second Messenger Systems Sepsis Signal Pathway Signal Transduction Smooth Muscle Smooth Muscle Myocytes Smooth Muscle Myosins Stimulus Stroke Syndrome Systemic blood pressure Testing Therapeutic Vascular Diseases Vascular Smooth Muscle Vascular resistance Vasodilation blood pressure regulation cardiovascular risk factor desensitization hemodynamics in vivo loss of function mortality mouse model myosin phosphatase notch protein novel novel therapeutic intervention pressure receptor receptor function response vasoconstriction

项目摘要

PROJECT SUMMARY/ABSTRACT Vascular smooth muscle (SM) and endothelial cells (EC) coordinate the molecular signals governing arterial vasoreactivity. The balance of constrictor and relaxant signals establishes vessel tone and directly influences systemic blood pressure in health and disease. Our laboratory has uncovered novel and paradoxical roles for Notch signaling in the vessel wall that influence arterial function. Specifically, SM Notch receptors triggered by SM Jagged1 ligand promote myosin light chain kinase (MLCK) expression and Ca2+ sensitization inducing myosin light chain (MLC) phosphorylation, the molecular signature of force production. Mice lacking SM Jagged1 feature dysregulated blood pressure and pressor responses and arteries exhibit impaired force generation. In contrast, EC Dll4 ligand stimulates expression of SM MYPT1, the regulatory subunit of myosin phosphatase (MP), favoring dephosphorylation of MLC and a relaxant phenotype. Moreover, EC Dll4-deficient arteries yield vasorelaxation deficits in a novel NO-independent manner. Together, these findings underscore instructional Notch signaling through heterotypic (EC-SM) and homotypic (SM-SM) cell interactions in the vessel wall and provide new knowledge in the molecular determinants of vasoregulation. The overall goal in this new project proposal is to define the physiologically relevant Notch ligand/receptor that modulates distinct arterial functions. In Aim 1, we determine the contribution of both SM and EC Jagged1 ligand and Notch1 receptor in regulation of constrictor and hemodynamic responses in vascular health and disease animal models. Aim 2 delineates the physiological role and mechanism of EC Dll4 ligand in mediating arterial relaxation. Finally, Aim 3 examines the molecular basis for Notch signaling-dependent control of myosin phosphatase activity via Ca2+ sensitization and/or desensitization. Experimental approaches include a full spectrum of in vivo, ex vivo and in vitro vascular analyses necessary for understanding relevant physiology and novel molecular mechanisms through which Notch pathway components regulate arterial function.

项目摘要/摘要血管平滑肌（SM）和内皮细胞（EC）协调了控制动脉的分子信号血管反应性。收缩和放松信号的平衡建立了船只的音调并直接影响健康和疾病的全身血压。我们的实验室发现了新颖和矛盾的作用影响动脉功能的容器壁中的凹口信号传导。具体而言，SM Notch受体触发 SM JAGGED1配体促进肌球蛋白轻链激酶（MLCK）表达和Ca2+敏化诱导肌球蛋白轻链（MLC）磷酸化，力产生的分子特征。缺乏SM的老鼠 JAGGED1特征功能失调的血压和压力反应和动脉表现出受损的力一代。相反，EC DLL4配体刺激肌球蛋白的调节亚基SM MyPT1的表达磷酸酶（MP），有利于MLC的去磷酸化和弛豫表型。此外，EC DLL4缺陷动脉以一种新型的无独立方式产生血管浮肿缺陷。在一起，这些发现强调了通过异型（EC-SM）和同型（SM-SM）细胞相互作用的教学凹槽信号传导血管壁并提供血管调节分子决定因素的新知识。总体目标这个新的项目建议是定义与生理相关的配体/受体调节不同动脉功能。在AIM 1中，我们确定SM和EC JAGGED1配体和Notch1的贡献血管健康和疾病动物中收缩和血液动力学反应调节中的受体型号。 AIM 2描述EC DLL4配体在介导动脉中的生理作用和机制松弛。最后，AIM 3检查了肌球蛋白的Notch信号依赖性控制的分子基础通过Ca2+敏化和/或脱敏的磷酸酶活性。实验方法包括完整的体内，体内和体外血管分析的频谱，用于了解相关生理学和新型分子机制通过该机制调节动脉功能。