New Signaling Networks in Vascular Smooth Muscle

血管平滑肌中的新信号网络

• 批准号: 10532301
• 负责人: Zygmunt S Derewenda
• 金额: $ 86.16万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532301
• 关键词: Acute; Address; Agonist; Animal Model; Arteries; Asthma; Attenuated; Blood Pressure; Blood Vessels; Blood capillaries; Blood flow; Comparative Study; Cytoplasm; 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; 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; blood pressure reduction; blood pressure regulation; cohort; defined contribution; hypertensive; improved; inhibitor; knowledge base; mechanical force; myosin phosphatase; new therapeutic target; novel; pharmacologic; pressure; response; rho; ribosomal protein S6 kinase kinase; vasoconstriction

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.

抽象的： 该提案重点关注我们发现的由 p90 核糖体 S6 激酶介导的新信号通路 (RSK2) 调节血管平滑肌 (VSM) 介导的血管阻力、肌源张力和血液 遵循这样的理性：结果有可能实现新的治疗目标。肌源性反应 小阻力动脉对于保护下游小动脉和毛细血管免受气压伤至关重要 血管内压力的过度变化。我们对控制信号通路的理解 肌源性和激动剂介导的血管收缩、血管阻力和血压稳态 不完整，该提案解决了我们知识库中的这一空白。我们的总体目标是确定 从机械和功能角度探讨 RSK2 对血管生理学和病理生理学的贡献 看法。我们的中心假设是 RSK2 激酶介导一个新的通路网络，从而导致 调节 VSM 收缩以响应肌源性压力和激动剂。这个假设是基于 初步数据确定了阻力动脉中增强收缩状态的三个 RSK2 目标：(1) RLC20，导致肌球蛋白跨桥功能的典型激活的直接增强； (2) NHE-1 Na+/H+ 交换剂，其磷酸化有助于 pHi 的增加，并伴随着 pHi 的增加 在细胞质 [Ca2+] 中，从而增强 MLCK 介导的途径； (3) 两个 RhoA 特异性核苷酸 交换因子，对 RhoA 介导的途径具有潜在的调节影响。我们的初步数据还 表明 RSK2 信号传导贡献了约 20% 的最大生肌力，并且来自 Rsk2-/- 小鼠的动脉 或用 RSK 抑制剂治疗的患者扩张程度更大，肌源张力和 RLC20 磷酸化降低，并且 与野生型小鼠相比，Rsk2-/- 小鼠的血压较低。我们假设这个非规范的 RSK2 通路增强经典 Ca2+/MLCK 和 RhoA/ROCK Ca2+ 敏化并与其交互作用 调节血管收缩和基础血压的途径。以下目标检验我们的假设： 目标 1： 确定 RSK2 如何响应灌注压和激动剂导致 VSM 收缩，其中 重点关注选定的磷酸化靶标，即 RLC20、NHE-1 和 RhoGEF。目标 2：评估 RSK2 有助于血压稳态。预计结果将建立并添加新的 RSK2 介导的 信号网络到规范 MLCK 和 RhoA/ROCK 信号通路，调节 VSM 音调和 血管收缩并为血管壁收缩病理提供可能的新治疗靶点。