The role of protease activated receptor 2 in the initiation and progression of abdominal aortic aneurysm

ABSTRACT (Project Summary) Rupture of abdominal aortic aneurysms (AAA) leads to sudden death in 15,000 to 30,000 men and women each year in the US, and this number is growing due to both an increase in the elderly population and our increasingly poor life-style choices, e.g. sedentary lifestyle and western diet, resulting in cardiovascular disease. Known risk factors for AAA include tobacco use, hypertension, male gender, and cardiovascular disease. However, the underlying cause of this condition is still poorly understood. Further, little progress has been made to identify any pharmacologic treatments which may benefit these patients leaving surgery as the only treatment option. Here, we define protease-activated receptor 2 (PAR2) as a novel mediator of aortic aneurysmal disease via potential regulation of CD34+ progenitor cells. PAR2, a seven transmembrane G protein-coupled receptor, promotes vascular inflammation via endothelial cell permeability, upregulation of cytokines, and vascular smooth muscle cell (VSMC) and macrophage activation. Increased PAR2 expression and activity is associated with cardiovascular diseases, known cardiovascular risk factors, and dysfunctional immunity. Our preliminary data shows PAR2 deficiency attenuates aortic diameter, aneurysm incidence, and rupture-induced death in two independent models of AAA via non-hematopoietic cells, with single cell RNA sequencing showing PAR2 highly localized to the VSMC compartment of aneurysmal tissues. Moreover, activation of PAR2 results in the localized release of transforming growth factor β1 (Tgfβ1) and decreased numbers of adventitial-derived CD34+ progenitor cells leading to structural failure of the aortic wall. Our overall hypothesis is that VSMC-derived PAR2 augments aneurysm pathology via decreased CD34-mediated myofibroblast tissue repair. Aim 1 of the grant will determine the effect of VSMC-specific PAR2 deletion and pharmacological PAR2 inhibition in mouse models of aneurysmal disease. Our second aim will delineate the role of PAR2 has in mediated CD34+ progenitor cells and their role on the initiation and progression of AAA. Completion of these aims will advance our understanding of the role of PAR2 and associate pathways on aneurysm initiation and progression and may lead to pharmaceutical interventions where none currently exist.