Abstract 114: Smooth Muscle Origin-specific Effects of LRP1 Deletion on Angiotensin II-induced Ascending Aortic Aneurysm

Abstract

Objective: Low-density lipoprotein receptor-related protein 1 (LRP1) plays a critical role in maintaining aortic wall integrity. LRP1 deletion in smooth muscle cells (SMCs) augments angiotensin II (AngII)-induced ascending aortic aneurysms. SMCs in the ascending aorta originate from both the second heart field (SHF) and cardiac neural crest (CNC). The purpose of this study was to determine whether LRP1 depletion in these two SMC origins has differential effects on AngII-induced ascending aortic aneurysm. Methods and Results: Mef2c-Cre was used to delete LRP1 in SMCs of SHF origin; while Wnt-1-Cre was utilized to delete LRP1 in SMCs of CNC origin in mice. Saline or AngII (1,000 ng/kg/min) was infused for 28 days into 12 - 14 week-old male mice with LRP1 depletion in either SHF or CNC origin as well as their wild type littermates. No mice died in saline-infused groups of either genotype. In the AngII-infused mouse group, LRP1 depletion in SMCs of SHF origin led to 38% death due to ascending aortic rupture, compared to a 4% rupture rate in wild type littermates (p = 0.002). In the survivors of AngII-infused group, LRP1 deletion in SMCs of SHF origin resulted in larger ascending aortic diameter compared to wild type littermates (1.6 ± 0.1 vs 2.0 ± 0.1 mm, p < 0.05), as measured by ultrasonography. In contrast to the increases of aortic rupture and luminal dilation in mice with LRP1 depletion in SMCs of SHF origin, LRP1 deletion in SMCs of CNC origin did not affect AngII-induced aortic rupture rate or luminal dilation, compared to wild type littermates. To explore potential signaling mechanisms on how LRP1 depletion in SMCs of SHF origin augments AngII-induced ascending aortic aneurysm, mice were infused with either saline or AngII for 24 hours, and ascending aortic tissues were harvested for Western blot analyses. Aortic LRP1 protein abundance was decreased in mice with LRP1 depletion in SMCs of SHF origin regardless of infusion. Although SMAD2 and ERK signaling contribute to aortic wall integrity, this short interval of AngII infusion did not change these activities in the aorta of SHF-SMC specific LRP1 deleted mice. Conclusion: LRP1 expression in SHF, but not in CNC, -derived SMCs exerts a critical role in the augmentation of AngII-induced ascending aortic aneurysm.