New Signaling Networks in Vascular Smooth Muscle

摘要： 本研究的重点是发现由p90核糖体S6激酶介导的新的信号通路 调节血管平滑肌（VSM）介导的血管阻力、肌源性张力和血液流变学的RSK 2 随着结果有可能提供新的治疗目标的理性而流动。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是至关重要的， 血管内压力的过度变化。我们对控制大脑的信号通路 肌源性和激动剂介导的血管收缩、血管阻力和血压稳态是 这一建议填补了我们知识基础中的这一空白。我们的总体目标是确定 RSK 2在血管生理学和病理生理学中的作用， perspective.我们的中心假设是RSK 2激酶介导了一个新的通路网络，导致 响应于肌源性压力和激动剂的VSM收缩的调节。这个假设是基于 初步数据鉴定了阻力动脉中增强收缩状态的三个RSK 2靶标：（1） RLC 20，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+交换器，其磷酸化有助于pHi的增加， 在胞质[Ca 2 +]中，从而增强MLCK介导的途径;和（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 这表明RSK 2信号传导贡献了约20%最大生肌力，且来自Rsk 2-/-小鼠的动脉 或用RSK抑制剂治疗的患者更扩张，具有降低的肌原性张力和RLC 20磷酸化， Rsk 2-/-小鼠的血压比野生型小鼠低。我们假设这个非经典的 RSK 2途径增强经典Ca 2 +/MLCK和RhoA/ROCK Ca 2 +-敏化并与之交叉对话 调节血管收缩和基础血压的途径。以下目标验证我们的假设：目标1： 确定RSK 2如何响应灌注压和激动剂而促进VSM收缩， 专注于选择磷酸化靶点，即RLC 20，NHE-1和RhoGEFs。目标2：评估 RSK 2对血压稳态的影响。预计结果将建立并增加新的RSK 2介导的 信号网络的经典MLCK和RhoA/ROCK信号通路调节VSM紧张和 血管收缩，并为血管壁的收缩性病理提供可能的新治疗靶点。

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.