Abstract 304: Differential Effects of LRP1 in AngII-induced Ascending Aortic PathologiesBetween Male and Female Mice: Lack of Association With Elastin Fragmentation

Abstract

Objective: Low-density lipoprotein receptor-related protein 1 (LRP1), a transmembrane protein, is important in maintaining elastin fiber integrity of the aortic wall. Smooth muscle cells (SMCs) of the ascending aorta are composed of the inner medial layers from the cardiac neural crest and the outer layers from the second heart field (SHF). LRP1 depletion in SMCs of male mice augments angiotensin II (AngII)-induced ascending aortic dilation and rupture attributed specifically to SMCs of SHF origin. The purpose of this study was to determine whether depletion of LRP1 in SHF-derived SMCs (SHF-SMC LRP1) has differential effects on AngII-induced aortic dilation, rupture, and elastin fragmentation between male and female mice. Methods and Results: Female LRP1 floxed mice were bred to male LRP1 floxed mice with Mef2c-Cre transgene to generate SHF-SMC LRP1 +/+ and -/- mice. Male and female mice at 12-14 weeks of age were infused with either saline or AngII (1,000 ng/kg/min) for 28 days (n = 12-31). Ascending aortic diameter (AoD) was measured by ultrasound, rupture was determined by necropsy, and elastin fragmentation was assessed by Movat’s staining. In male mice of both genotypes, AoD and elastin breaks were increased by AngII infusion, and AoD was positively correlated with elastin fragmentation (r 2 = 0.48, p < 0.001). SHF-SMC LRP1 deletion augmented aortic dilation, rupture rate, and elastin fragmentation in AngII-infused male mice. In females, AngII infusion increased AoD in SHF-SMC LRP1 -/- mice, but not in their wild type controls. AngII-induced elastin fragmentation did not differ between SHF-SMC LRP1 +/+ and -/- female mice, and no correlation between AoD and elastin fragmentation was detected (r 2 = 0.01, p = 0.88). Despite the extent of AngII-induced elastin fragmentation that was equivalent to that in males, aortic rupture is lower in female than in male LRP1 deleted mice (9 vs 38%, p = 0.02). Conclusion: In male mice, AngII infusion promotes dilation and rupture of ascending aorta that is augmented in SHF-SMC LRP1-/- mice and positively associated with elastin fragmentation. However, AngII only promotes ascending aortic dilation in female mice with SHF-SMC LRP1 deletion, despite elastin fragmentation being equivalent between SHF-SMC LRP1 +/+ and -/- mice.