Abstract 292: LRP1 Prevents Aortic And SMA Aneurysms By Modulating Excessive Ang-II Signaling

Objectives: LRP1 (low-density lipoprotein receptor-related protein 1) is known to contribute to vascular homeostasis and plays a protective role against the development of aneurysms. LRP1 has specifically been associated with abdominal aortic aneurysms in GWAS studies. We and others have also previously reported that mice with a conditional smooth muscle cell (SMC) knock-out of LRP1 (smLRP1-/-) exhibit vascular wall dysfunction and aortic dilation. In this study, we sought to investigate the molecular mechanisms by which LRP1 regulates vessel wall integrity in hopes of identifying potential therapeutic targets against aneurysm progression. Approach and Results: Analysis of proteomic data of the descending thoracic aorta, abdominal aorta, and superior mesenteric artery (SMA) of smLRP1-/- mice confirmed excess activation of the angiotensin signaling pathway. To verify these observations, we designed experiments to determine if losartan, an angiotensin-II receptor blocker, could prevent aneurysm progression in smLRP1-/- mice. Following treatment, we analyzed the aortic vasculature from LRP1+/+ and smLRP1-/- adult mice (16-weeks of age) with or without treatment. Without losartan, smLRP1-/- mice developed spontaneous aortic and SMA aneurysms as demonstrated by increased vessel dilation, vessel medial thickening and significant fragmentation of the elastic lamina. We found that when treated with losartan, smLRP1-/- mice had a complete restoration of medial layer thickness and a partial decrease of elastin fragmentation compared to untreated smLRP1-/- mice. Furthermore, losartan completely blocked SMA aneurysm formation in smLRP1-/- mice. Conclusions: Our findings suggest a critical role for LRP1 in maintaining vascular homeostasis and preventing aneurysm formation through its regulation of the angiotensin signaling pathway. Further studies will need to investigate the connection between LRP1 and the angiotensin signaling pathway in aneurysm formation to further understand the complex pathophysiology and potentially develop effective therapeutic targets for this disease.