Arterial Vasoregulation by Notch Signaling

通过 Notch 信号调节动脉血管

• 批准号: 10399591
• 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
• 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/10399591
• 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

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.

项目总结/摘要 血管平滑肌（SM）和内皮细胞（EC）协调调节动脉粥样硬化的分子信号， 血管反应性收缩和舒张信号的平衡建立血管张力并直接影响 健康和疾病中的全身血压。我们的实验室已经发现了新的和矛盾的作用， 血管壁中影响动脉功能的Notch信号传导。具体来说，SM Notch受体由 SM Jagged 1配体促进肌球蛋白轻链激酶（MLCK）表达及钙致敏作用 肌球蛋白轻链（MLC）磷酸化，力产生的分子特征。缺乏SM的小鼠 锯齿状1的特征是血压和升压反应失调，动脉表现出受损的力量 一代相反，EC Dll 4配体刺激SM MYPT 1的表达，SM MYPT 1是肌球蛋白的调节亚基， 磷酸酶（MP），有利于MLC的去磷酸化和松弛表型。此外，EC D114缺陷型 动脉以一种新的NO非依赖性方式产生血管舒张缺陷。总之，这些发现强调了 通过异型（EC-SM）和同型（SM-SM）细胞相互作用的指导性Notch信号传导， 并提供了血管调节的分子决定因素的新知识。总体目标是 这个新的项目提案是定义生理相关的Notch配体/受体， 动脉功能在目的1中，我们确定SM和EC Jagged 1配体和Notch 1的贡献， 受体在血管健康和疾病动物缩血管和血流动力学反应中的调节作用 模型目的2阐明EC Dll 4配体在介导动脉粥样硬化中的生理作用和机制 放松.最后，目标3研究了Notch信号依赖性控制肌球蛋白的分子基础 磷酸酶活性通过Ca 2+敏化和/或脱敏。实验方法包括一个完整的 了解相关生理学所需的体内、离体和体外血管分析范围， Notch途径成分调节动脉功能的新分子机制。