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

• 批准号: 10377625
• 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
• 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/10377625
• 关键词: Adrenergic Receptor; Affect; Arteries; Blood Vessels; CCL22 gene; CCL3 gene; Cardiovascular Physiology; Cardiovascular system; Cell membrane; Characteristics; Clinical; Complex; Critical Illness; Development; Event; Excision; Functional disorder; Hemorrhagic Shock; Impairment; Inflammatory Response; Knowledge; Ligands; Liquid substance; Mediating; Molecular; Molecular Target; Muscle Contraction; Myography; Pathway interactions; Patients; Pharmacology; Phase; RANTES; Regulation; Resistance; Resuscitation; Role; Shock; Signal Transduction; Smooth Muscle Myocytes; Testing; Trauma patient; Traumatic Hemorrhage; Tunica Media; Vascular Smooth Muscle; Vasoconstrictor Agents; beta-arrestin; biological adaptation to stress; blood pressure regulation; cardiovascular collapse; chemokine; chemokine receptor; constriction; desensitization; early detection biomarkers; hemodynamics; improved; in vivo; novel therapeutic intervention; novel therapeutics; pressure; prevent; receptor; receptor function; recruit; vascular contributions

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.

项目总结/摘要 血管张力的丧失是失血性休克和体液性休克时心血管衰竭的特征 复苏（HS/R）。α1-肾上腺素能受体（AR）的功能障碍和脱敏被认为是 血管扩张性休克的标志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（CCL 2）、CCL 3、CCL 5和CCL 22已经被研究。 被鉴定为HS/R初始炎症反应的关键驱动因素，并作为早期生物标志物， 幸存和非幸存的创伤患者。其病理生理和分子机制 然而，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（CCR 1）、CCR 2和CCR 4，它们是CCL 2的受体， CCL 3、CCL 5和CCL 22与阻力动脉图尼卡中膜中的α1-AR形成异聚体复合物。 我们提供的初步证据表明，CCR 2的激活拮抗α1-AR介导的血管收缩， α1-AR是一种分子信号传导事件，它启动了血管阻力的清除， 质膜α1-AR。这导致了我们的主要假设，即趋化因子的释放在早期 HS/R时相通过激活其CRs损害血管张力和血压调节， 与血管平滑肌细胞（VSMC）中α1-AR相互作用并调节α1-AR。这意味着药理学 靶向与α1-AR相互作用的CR将提供新的治疗选择，以稳定血管张力， 血液动力学、预防心血管衰竭和改善HS后复苏。为了验证这个假设， 我们提出了三个具体的目标：1）确定α1-AR的CR异聚化伴侣如何调节 离体血管功能。我们将使用压力性肌造影术和分离的阻力动脉作为测试 该平台用于定义所鉴定的CR异聚化伴侣在内源性血管内皮细胞生长因子调节中的作用。 功能和血管加压素反应性。2)为了测试CR的药理学靶向如何 α1-AR的异聚化配偶体在体内调节心血管功能。我们将决定如何 阻断和激活CR异聚化配偶体影响正常心血管功能，血管加压素 反应性和心血管功能。3)为了确定分子机制， 其中α1-AR的CR异聚化配偶体调节α1-AR的功能。康贝特人将以 确定的CRs和α1-AR之间的串扰机制，并阐明CR α1-AR的异聚化配偶体调节α1-AR诱导的信号传导和VSMC收缩。新知识 从这一建议中获得的信息将促进我们对血管功能调节的理解， 新的分子靶点可用于改善HS/R期间的血压控制， 血液动力学不稳定的危重病人。