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New Signaling Networks in Vascular Smooth Muscle

血管平滑肌中的新信号网络

基本信息

批准号：
10531647
负责人：
Zygmunt S Derewenda
金额：
$ 14.25万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-15 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10531647
关键词：
Acute Address Agonist Animal Model Arteries Asthma Attenuated Blood Pressure Blood Vessels Blood capillaries Blood flow Comparative Study Data Development Disease Drug Targeting Dysbarism Functional disorder G-Protein-Coupled Receptors Goals Guanine Nucleotide Exchange Factors Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Health Hypertension Hypotension Knockout Mice Knowledge Mediating Mission Mus Muscle Contraction Muscle Tonus Myosin ATPase Myosin Light Chain Kinase Myosin Regulatory Light Chains NG-Nitroarginine Methyl Ester Nucleotides Outcome Pathologic Pathology Pathway interactions Patients Perfusion Pharmaceutical Preparations Pharmacology Phosphorylation Phosphotransferases Physiological Physiology Protein Dephosphorylation Protein Isoforms Public Health RPS6KA gene Regulation Relaxation Research Resistance Ribosomal Protein S6 Kinase Ribosomes Role Scheme Shock Signal Pathway Signal Transduction Smooth Muscle Smooth Muscle Myocytes Testing Therapeutic Therapeutic Intervention United States National Institutes of Health Up-Regulation Vascular Smooth Muscle Vascular resistance Vasodilation Wild Type Mouse arteriole base blood pressure reduction blood pressure regulation cohort defined contribution hypertensive improved inhibitor knowledge base mechanical force myosin phosphatase new therapeutic target novel pressure response rho ribosomal protein S6 kinase kinase vasoconstriction

项目摘要

Abstract: This proposal focuses on our discovery of new signaling pathways mediated by the p90 ribosomal S6 kinase (RSK2) that regulate vascular smooth muscle (VSM) mediated vascular resistance, myogenic tone and blood flow with the rational that outcomes have potential to deliver new therapeutic targets. The myogenic response of small resistance arteries is critical for protection of downstream arterioles and capillaries against barotrauma due to excessive changes in intravascular pressure. Our understanding of the signaling pathways that control myogenic and agonist-mediated vasoconstriction, vascular resistance and blood pressure homeostasis are incomplete and this proposal addresses this gap in our knowledge base. Our overall objective is to determine the contribution of RSK2 to vascular physiology and pathophysiology from a mechanistic and functional perspective. Our central hypothesis is that RSK2 kinase mediates a novel network of pathways that result in regulation of VSM contraction in response to myogenic pressure and to agonists. This hypothesis is based on preliminary data identifying three RSK2 targets in resistance arteries which potentiate the contractile state: (1) RLC20, leading to direct augmentation of the canonical activation of myosin cross-bridge function; (2) NHE-1 Na+/H+ exchanger, the phosphorylation of which contributes to an increase in pHi associated with an increase in cytosolic [Ca2+], thereby potentiating the MLCK-mediated pathway; and (3) two RhoA-specific nucleotide exchange factors, with potential regulatory impact on the RhoA-mediated pathway. Our preliminary data also suggest that RSK2 signaling contributes ~20% of maximal myogenic force and that arteries from a Rsk2-/- mouse or treated with RSK inhibitors are more dilated, have reduced myogenic tone and RLC20 phosphorylation and that Rsk2-/- mice have lower blood pressure compared to wild-type mice. We hypothesize that this non-canonical RSK2 pathway augments and cross talks with the canonical Ca2+/MLCK and RhoA/ROCK Ca2+-sensitization pathways to regulate vasoconstriction and basal BP. The following aims test our hypotheses: Aim 1: To determine how RSK2 contributes to VSM contraction in response to perfusion pressure and agonists, with a focus on select phosphorylation targets, i.e. RLC20, NHE-1 and RhoGEFs. Aim 2: To assess the contribution of RSK2 to blood pressure homeostasis. Outcomes are expected to establish and add a new RSK2 mediated signaling network to the canonical MLCK and RhoA/ROCK signaling pathways regulating VSM tone and vasoconstriction and to provide possible new therapeutic targets for contractile pathologies of the vessel wall.

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