Contributions of vascular chemokine receptors to cardiovascular function after traumatic-hemorrhagic shock

血管趋化因子受体对创伤失血性休克后心血管功能的贡献

基本信息

批准号：
10641113
负责人：
Matthias Majetschak
金额：
$ 12.48万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
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：
2020-09-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10641113
关键词：
Accidental Injury Adrenergic Receptor Affect Agonist Arteries Biological Assay Bioluminescence Blood Vessels CC chemokine receptor 4 CCL22 gene CCL3 gene CXCR4 Receptors Cardiovascular Physiology Cardiovascular system Cell membrane Cell physiology Cessation of life Characteristics Clinical Complex Critical Illness Data Development Disease Energy Transfer Event Excision Family Functional disorder G-Protein-Coupled Receptors Hemorrhage Hemorrhagic Shock Human Impairment Inflammation Inflammatory Inflammatory Response Knowledge Ligands Ligation Liquid substance Mediating Molecular Molecular Target Muscle Contraction Myography Operative Surgical Procedures Organ Pathway interactions Patients Pharmacology Phase Physiological Play Process RANTES Regulation Resistance Resolution Resuscitation Role Series Shock Signal Transduction Smooth Muscle Myocytes Testing Trauma Trauma patient Traumatic Brain Injury Traumatic Hemorrhage Tunica Media Vascular Smooth Muscle Vascular remodeling Vasoconstrictor Agents base beta-arrestin biological adaptation to stress blood pressure control blood pressure regulation cardiovascular collapse chemokine chemokine receptor constriction desensitization early detection biomarkers experimental study hemodynamics improved in vivo insight leukocyte activation member novel novel therapeutic intervention novel therapeutics pressure prevent preventable death receptor receptor function recruit single molecule vascular contributions vasoconstriction

项目摘要

Project Summary/Abstract Loss of vascular tone is characteristic for cardiovascular collapse during hemorrhagic shock and fluid resuscitation (HS/R). Dysfunction and desensitization of α1-adrenergic receptors (ARs) is considered the hallmark in the development of vasodilatory shock. The mechanisms responsible for α1-AR dysfunction are unknown. The chemokines (C-C motif) chemokine ligand 2 (CCL2), CCL3, CCL5 and CCL22 have been identified as key drivers of the initial inflammatory response to HS/R, and as early biomarkers that segregate surviving and non-surviving trauma patients. The pathophysiological and molecular mechanisms underlying these important clinical correlations, however, remain to be determined. We discovered that the chemokine receptors (CRs) (C-C motif) chemokine receptor 1 (CCR1), CCR2 and CCR4, which are receptors for CCL2, CCL3, CCL5 and CCL22, form heteromeric complexes with α1-AR in the tunica media of resistance arteries. We provide preliminary evidence that activation of CCR2 antagonizes α1-AR mediated constriction of isolated resistance arteries and cross-recruits b-arrestin to α1-AR, a molecular signaling event that initiates removal of α1-AR from the plasma membrane. This leads to our main hypothesis that chemokine release during early phases of HS/R impairs vascular tone and blood pressure regulation through activation of their CRs, which interact with and regulate α1-AR in vascular smooth muscle cells (VSMCs). This implies that pharmacological targeting of the CRs that interact with α1-AR will provide new therapeutic options to stabilize vascular tone and hemodynamics, prevent cardiovascular collapse and improve resuscitation after HS. To test this hypothesis, we propose three specific aims: 1) To determine how the CR heteromerization partners of α1-AR regulate vascular function ex vivo. We will utilize pressure myography with isolated resistance arteries as a test platform to define the roles of the identified CR heteromerization partners in the regulation of intrinsic vascular function and vasopressor responsiveness. 2) To test how pharmacological targeting of the CR heteromerization partners of α1-AR modulates cardiovascular function in vivo. We will determine how blockade and activation of CR heteromerization partners affect normal cardiovascular function, vasopressor responsiveness and cardiovascular function during HS/R. 3) To determine the molecular mechanisms by which the CR heteromerization partners of α1-AR regulate α1-AR function. We will determine the mechanisms of cross-talk between the identified CRs and α1-AR, and elucidate the pathways by which the CR heteromerization partners of α1-AR modulate α1-AR-induced signaling and VSMC contraction. New knowledge gained from this proposal will advance our understanding of the regulation of vascular function and identify new molecular targets that could be used to improve blood pressure control during HS/R, and in hemodynamically instable critically ill patients in general.

项目概要/摘要血管张力丧失是失血性休克和液体流失期间心血管崩溃的特征 α1-肾上腺素受体（AR）的功能障碍和脱敏被认为是复苏（HS/R）。血管舒张性休克发生的标志是 α1-AR 功能障碍的机制。趋化因子（C-C 基序）趋化因子配体 2 (CCL2)、CCL3、CCL5 和 CCL22 未知。被确定为 HS/R 初始炎症反应的关键驱动因素，以及分离的早期生物标志物幸存和未幸存的创伤患者的病理生理学和分子机制。然而，这些重要的临床相关性仍有待确定。受体 (CR)（C-C 基序）趋化因子受体 1 (CCR1)、CCR2 和 CCR4，它们是 CCL2 的受体， CCL3、CCL5 和 CCL22 与阻力动脉中膜中的 α1-AR 形成异聚复合物。我们提供了初步证据表明 CCR2 的激活可以拮抗 α1-AR 介导的分离的收缩阻力动脉和交叉招募 β-arrestin 到 α1-AR，这是一种分子信号事件，可启动去除 α1-AR 来自质膜，这导致我们的主要假设是趋化因子在早期释放。 HS/R 阶段通过激活 CR 损害血管张力和血压调节，与血管平滑肌细胞 (VSMC) 中的 α1-AR 相互作用并对其进行调节，这意味着药理学作用。靶向与 α1-AR 相互作用的 CR 将为稳定血管张力和血流动力学，预防心血管衰竭并改善 HS 后的复苏。我们提出了三个具体目标：1）确定α1-AR的CR异聚伙伴如何调节我们将利用压力肌动描记法和孤立的阻力动脉作为测试。定义已确定的 CR 异聚化伙伴在内血管调节中的作用的平台功能和升压药反应性 2) 测试 CR 的药理学靶向性。我们将确定 α1-AR 的异聚伙伴如何调节体内心血管功能。 CR异聚化伴侣的阻断和激活影响正常心血管功能、血管升压药 HS/R 期间的反应性和心血管功能 3) 通过以下方式确定分子机制。 α1-AR 的 CR 异聚化伙伴调节 α1-AR 功能。确定的 CR 和 α1-AR 之间的串扰机制，并阐明 CR 的途径 α1-AR 的异聚化伙伴调节 α1-AR 诱导的信号传导和 VSMC 收缩。从该提案中获得的成果将增进我们对血管功能调节的理解并确定新的分子靶点可用于改善 HS/R 期间的血压控制，以及一般是血流动力学不稳定的危重病人。