Regulation of vascular function after traumatic-hemorrhagic shock and during inflammation

Project Summary/Abstract Numerous disease processes impair the regulation of vascular function, leading to abnormally high or low blood pressure. While hypertension is considered as the most important risk factor for global burden of disease, severe hypotension and vasodilatory shock are of major importance in critical illness. Morbidity and mortality of vasodilatory shock remain unacceptably high and treatment strategies have not been improved since decades. Thus, a better understanding of the mechanisms that regulate vascular function is a prerequisite for the development of improved treatment strategies for critically ill patients. Although dysfunction of a1-adrenergic receptors (AR) is thought to constitute the hallmark in the development of vasodilatory shock, the molecular mechanisms leading to impaired α1-AR function have been unknown. Similarly, information on the regulation of other important G protein-coupled receptors (GPCRs) that mediate vasoconstrictor responses, such as arginine vasopressin receptor (AVPR) 1A or angiotensin II receptor 1, during the cardiovascular stress response and the development of vascular dysfunction in critically ill patients has not been available. The main goal of the PI’s research program is to understand the molecular mechanisms that regulate vascular function during the cardiovascular stress response and to identify new therapeutic approaches to stabilize vascular function in critically ill patients. The PI’s laboratory discovered that chemokines and their receptors regulate vascular GPCRs that mediate the effects of key stress hormones, i.e. catecholamines/α1-ARs and arginine vasopressin/AVPR1A, and identified hetero-oligomerization between chemokine receptors (CRs) and vasopressor receptors as a molecular mechanism underlying their cross-talk. In this MIRA application, we propose to build upon our recent progress in the field and to address critical knowledge gaps regarding the prevalence, assembly and molecular signaling properties of hetero-oligomeric complexes between CRs and vasopressor receptors, and to elucidate their relevance in health and disease processes. We will focus primarily on the roles of CRs in the regulation of vasopressor function, but also plan to expand studies on the roles of vasopressor receptors in the regulation of CR function. We propose a multi-faceted and translationally relevant approach, spanning from state-of-the-art molecular biology techniques to analyze receptor heteromer formation and function at the molecular and cellular level to in vivo animal models and analyses of the function of freshly isolated vascular smooth muscle cells and intact resistance arteries from animals and patients. We believe that this project has the potential to establish a new paradigm in the understanding of the regulation of vascular smooth muscle function in health and disease and is likely to identify new molecular targets to modulate vascular function and blood pressure regulation in various disease processes.