TRP channels in the regulation of vascular tone

TRP 通道在血管张力调节中的作用

• 批准号: 10654013
• 负责人: David X. Zhang
• 金额: $ 53.07万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-04 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654013
• 关键词: Address; Adipose tissue; Aging; Animal Disease Models; Animal Model; Arachidonic Acids; Arteries; Atherosclerosis; Binding; Binding Sites; Blood Vessels; Cause of Death; Cell Separation; Cells; Compensation; Coronary; Coronary Arteriosclerosis; Cyclic AMP-Dependent Protein Kinases; Disease; Electrophysiology (science); Endothelial Cells; Endothelium; Enzymes; Equilibrium; Functional disorder; Funding; Gene Expression; Genetic Polymorphism; Goals; Health; Homeostasis; Homologous Gene; Human; Hydrogen Peroxide; Image; Impairment; Inflammation; Ion Channel; Knock-out; Ligands; Mass Spectrum Analysis; Mediating; Mediator; Metabolism; Microcirculation; Microvascular Dysfunction; Mitochondria; Modeling; Molecular; Mutagenesis; Myocardial Ischemia; NADPH Oxidase; Nitric Oxide; Outcome; Oxidation-Reduction; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Phospholipase A2; Phosphorylation; Play; Process; Production; Protein Isoforms; Proteins; Reactive Oxygen Species; Regulation; Role; Signal Transduction; Small Interfering RNA; Structural Models; Structure; TRP channel; Testing; Transfection; Vanilloid; Variant; Vascular Diseases; Vasodilation; Vasodilator Agents; Woman; acute stress; analog; arteriole; design; eicosanoid metabolism; endothelial dysfunction; gain of function; human disease; human model; human tissue; improved; in vivo; inhibitor; innovation; insight; lipophilicity; men; mimetics; molecular modeling; novel; novel strategies; outcome prediction; patch clamp; pharmacologic; receptor; release factor; structural biology; synergism; targeted treatment; transcriptome sequencing; vasomotion

Vascular homeostasis is critically dependent upon vasodilator factors released from the endothelium. The most prominent of these factors is nitric oxide (NO), which is the main barometer of endothelial function and becomes impaired in a broad range of diseases including coronary artery disease (CAD). In the human coronary and adipose microcirculation, we have demonstrated a novel process where loss of NO-dependent flow-mediated dilation (FMD) in subjects with CAD is compensated by the production of hydrogen peroxide (H2O2) from endothelial mitochondria and subsequent H2O2-dependent dilation. Although both are vasodilators, H2O2, in opposition to NO, generally promotes cell activation, inflammation, and atherosclerosis, and thus understanding mechanisms responsible for this transition from NO to H2O2 may be key to developing novel strategies to improve endothelial function in patients with CAD. The overall goal of this project is to elucidate the signaling mechanisms that regulate the vasodilator switch from NO to H2O2 during CAD. Building on findings from the last cycle, this proposal is designed to determine intracellular pathways responsible for a previously unappreciated gain of function of endothelial transient receptor potential vanilloid 4 (TRPV4) channels and its contribution to vasodilator switch in CAD. We will test the central hypothesis that a synergy of shear-sensitive phospholipase A2-derived arachidonic acid and NADPH oxidase signaling promotes TRPV4 activation and subsequent H2O2-dependent dilation while cross-inhibiting NO-dependent dilation in CAD arterioles. Further, NADPH oxidases as novel aging- and CAD-associated upstream regulators play a critical role in initiating the switch. This application brings together expertise in vasomotion regulation, human microcirculation, and ion channel structural biology to identify novel molecular mechanisms and interactions that regulate vasodilator switch during CAD. Specific Aims: (1) we will determine the molecular mechanism of TRPV4 activation and arteriolar dilation by flow; and (2) we will determine how NADPH oxidases regulate TRPV4 activation and conversion from NO to H2O2 as mediator of FMD in CAD arterioles. Studies will be conducted on freshly isolated human arterioles and endothelial cells as well as in vivo animal models, using a multifaceted approach incorporating isolated vessel reactivity, Ca2+ imaging, patch-clamping electrophysiology, mass spectrometry, RNA-Seq, mutagenesis, and ion channel molecular modeling. Significance: our proposed studies will provide insight into fundamental mechanisms regulating human microvascular function in health and disease and potentially impact our approach to coronary microvascular dysfunction associated with CAD and a variety of other vascular pathologies.

血管稳态严重取决于内皮释放的血管舒张因子。最多 这些因素中突出的是一氧化氮（NO），这是内皮功能的主要晴雨表，成为 在包括冠状动脉疾病（CAD）在内的广泛疾病中受损。在人类冠状动脉和 脂肪微循环，我们证明了一个新的过程，其中无依赖性流量介导的损失 患有CAD的受试者的扩张（FMD）通过过氧化氢（H2O2）的产生得到补偿。 内皮线粒体和随后的H2O2依赖性扩张。尽管两者都是血管扩张剂，但H2O2， 反对NO，通常会促进细胞激活，炎症和动脉粥样硬化，从而理解 从NO到H2O2过渡的机制可能是制定新型策略以改善的关键 CAD患者的内皮功能。该项目的总体目标是阐明信号传导机制 该调节加速器在CAD期间从NO转移到H2O2。基于上一个周期的发现，这是 建议旨在确定负责先前未批准的增益的细胞内途径 内皮瞬态受体电势香草素4（TRPV4）通道的功能及其对血管扩张剂的贡献 切换CAD。我们将测试中心假设，即剪切敏感磷脂酶A2衍生的协同作用 花生四烯酸和NADPH氧化酶信号促进TRPV4激活，随后的H2O2依赖性 在CAD小动脉中不依赖于无依赖性扩张的同时扩张。此外，NADPH氧化酶是新型衰老 与CAD相关的上游调节器在启动开关中起着至关重要的作用。此应用程序带来 在血管舒张调节，人体微循环和离子通道结构生物学方面共同识别 在CAD期间调节血管扩张转换的新型分子机制和相互作用。具体目的：（1）我们 将确定TRPV4激活和小动脉扩张的分子机制； （2）我们将 确定NADPH氧化酶如何调节TRPV4的激活和从NO转换为H2O2作为介体 CAD动脉中的FMD。研究将对新鲜分离的人动脉和内皮细胞进行研究 以及在体内动物模型中，使用多方形的方法，结合了孤立的血管反应性Ca2+ 成像，贴片夹电生理学，质谱，RNA序列，诱变和离子通道 分子建模。意义：我们提出的研究将提供对基本机制的见解 调节人类的微血管在健康和疾病中的功能，并有可能影响我们的冠状动脉方法 与CAD和多种其他血管病理相关的微血管功能障碍。

项目成果

H2O2 is the transferrable factor mediating flow-induced dilation in human coronary arterioles.

• DOI: 10.1161/circresaha.110.237636
• 发表时间: 2011-03-04
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Liu Y;Bubolz AH;Mendoza S;Zhang DX;Gutterman DD
• 通讯作者: Gutterman DD

Characterization of blood pressure and endothelial function in TRPV4-deficient mice with l-NAME- and angiotensin II-induced hypertension.

• DOI: 10.1002/phy2.199
• 发表时间: 2014-01-01
• 期刊: PHYSIOLOGICAL REPORTS
• 影响因子: 2.5
• 作者: Nishijima, Yoshinori;Zheng, Xiaodong;Lund, Hayley;Suzuki, Makoto;Mattson, David L;Zhang, David X
• 通讯作者: Zhang, David X

NADPH oxidase 4 contributes to TRPV4-mediated endothelium-dependent vasodilation in human arterioles by regulating protein phosphorylation of TRPV4 channels.

• DOI: 10.1007/s00395-022-00932-9
• 发表时间: 2022-04-25
• 期刊: Basic research in cardiology
• 影响因子: 9.5

Prolonged endothelial-dysfunction in human arterioles following infection with SARS-CoV-2.

• DOI: 10.1093/cvr/cvab339
• 发表时间: 2022-01-07
• 期刊: Cardiovascular research
• 影响因子: 10.8
• 作者: Nishijima Y;Hader SN;Hanson AJ;Zhang DX;Sparapani R;Gutterman DD;Beyer AM
• 通讯作者: Beyer AM

Myocardin and Kv1 Channels: A Paradigm Shift in Treating Vascular Smooth Muscle Cell-Related Proliferative Disease?

心肌素和 Kv1 通道：治疗血管平滑肌细胞相关增殖性疾病的范式转变？

• DOI: 10.1161/atvbaha.119.313531
• 发表时间: 2019
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Zhang,DavidX;Gutterman,DavidD
• 通讯作者: Gutterman,DavidD