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.

项目摘要/摘要血管张力的丧失是出血性休克和液体中心血管塌陷的特征复苏（HS/R）。 α1-肾上腺素受体（ARS）的功能障碍和脱敏被认为是血管舒张冲击发展的标志。负责α1-ar功能障碍的机制是未知。趋化因子（C-C基序）趋化因子配体2（CCL2），CCL3，CCL5和CCL22是被确定为对HS/R的初始炎症反应的关键驱动因素，以及隔离的早期生物标志物存活和非残疾创伤患者。基础的病理生理和分子机制但是，这些重要的临床相关性仍有待确定。我们发现趋化因子受体（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在电阻动脉的Tunica培养基中与α1-AR形成杂体复合物。我们提供了初步证据，表明CCR2的激活拮抗了分离的α1-ar介导的收缩抗性动脉和交叉素质B- arrestin至α1-ar，这是一个分子信号事件，启动去除质膜的α1-ar。这导致了我们的主要假设，即早期趋化因子释放 HS/R的阶段通过激活其CRS而损害血管张力和血压调节，而CRS的阶段与血管平滑肌细胞（VSMC）中的α1-AR相互作用并调节。这意味着药物与α1-AR相互作用的CR的靶向将提供新的治疗选择，以稳定血管张力和血液动力学，防止心血管塌陷并改善HS后的复苏。为了检验这一假设，我们提出了三个具体目的：1）确定α1-AR的CR异构化伙伴如何调节血管功能离体。我们将利用孤立的电阻动脉的压力metraphics作为测试定义已确定的CR异构化伙伴在固有血管调节中的作用的平台功能和加压器响应能力。 2）测试CR的药物靶向 α1-ar的异晶伴侣在体内调节心血管功能。我们将确定如何 CR异构化伴侣的封锁和激活会影响正常的心血管功能，加压剂 HS/R期间的反应性和心血管功能。 3）确定分子机制 α1-AR的Cr异构化伙伴调节α1-AR功能。我们将确定已识别的CR和α1-AR之间的串扰机制，并阐明了CR的途径 α1-ar的异构化伴侣调节α1AR诱导的信号传导和VSMC收缩。新知识从这项建议中获得的将提高我们对血管功能调节的理解，并确定可用于改善HS/R期间血压控制的新分子靶标，在一般而言，血液动力学的重症患者。