The Role of the Endoplasmic Reticulum Stress Response in Abdominal Aortic Aneurysm Development

Abdominal aortic aneurysms (AAA) are a potentially lethal vascular disease common in the Veteran population that if left untreated, can progress to aortic rupture which has a mortality rate over 80%. Equally alarming, there are currently no medical therapies available to limit AAA growth, due in large part to a lack of understanding of the molecular mechanisms underlying AAA development. Thus, a critical need exists to understand the mechanisms that govern AAA expansion. One key hallmark of AAAs is interactions between invading immune cells, mainly macrophages, and vascular smooth muscle cells (VSMCs) resulting in smooth muscle cell dysfunction and apoptosis. We present data using human single-cell RNA sequencing and two murine AAA models, that within aortic tissue there is upregulation of the PERK/eIF2α/ATF4 endoplasmic reticulum (ER) cellular stress response in VSMCs which in turn augments CHOP-mediated ER stress induced VSMC apoptosis. Further we have identified that the transcriptionally activating chromatin modifying enzyme, MLL1, is elevated in aortic VSMCs increasing CHOP expression and associated VSMC dysfunction. These results have led to our hypothesis that during AAA development inflammatory cytokine signaling activates the eIF2α/ATF4 VSMC ER stress response and MLL1-mediated CHOP expression promoting VSMC apoptosis and resulting AAA expansion. We further postulate that inhibition of the ER stress response pathway or MLL1 in VSMCs will reduce cellular dysfunction thereby decreasing AAA formation. This hypothesis will be investigated via the following specific aims: Aim 1: Elucidate the impact of ER stress response signaling via PERK/eIF2α/ATF4 on VSMC apoptosis in human and murine AAAs. Aim 2: Determine the MLL1-mediated regulation of ER stress associated CHOP gene expression in human and murine AAA VSMCs. Aim 3: Examine the therapeutic efficacy of inhibition of the ATF4-MLL1-CHOP pathway on AAA expansion. In this translational approach, our data will pave the way for the development of promising preventive therapeutic agents aimed at targeting VSMC dysfunction and thereby prevent AAA expansion and rupture. In addition to furthering our understanding of the role of the ER stress response in AAA development, this proposal will also support my continued training and development to establish myself as an independent investigator in the field of aortic aneurysm pathology and vascular biology.