Abstract 128: LRP1 Deletion in Smooth Muscle Cells of the Outer Aortic Media Promotes Angiotensin II-induced Thoracic Aortic Aneurysm

Abstract

Objective: Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional protein that is linked to several vascular pathologies. LRP1 deletion in smooth muscle cells (SMCs) accelerates angiotensin II (AngII)-induced thoracic aortic aneurysm (TAA). In association with TAA formation, there is medial thickening that is characterized by a transmural gradient in which pathology progressively increases from lumen to adventitial aspect. We hypothesized that deletion of LRP1 in the outer medial layers of the proximal thoracic aorta has a pivotal role in the pathogenesis of TAA. The aim of this study was to determine whether LRP1 deletion in the outer media accelerates AngII-induced TAA formation. Methods and Results: SMCs in the outer media of the ascending aorta are derived from the second heart field, as demonstrated by lineage tracing studies using Cre under the control of Mef2c. Therefore, we used Mef2c-driven Cre to delete LRP1 in SMCs of the outer medial layers. Female LRP1 flox/flox mice were bred to male Mef2c-Cre1/0 mice to generate study mice. We first confirmed LRP1 deletion in Cre1/0 mice by both immunostaining and Western blot. LRP1 was expressed ubiquitously across smooth muscle cells of all aortic medial layers in Cre 0/0 mice. In mice expressing Mef2c-Cre, aortic LRP1 protein was detected only in SMCs of the inner laminar medial layers. Western blotting demonstrated LRP1 protein abundance in Cre expressing mice was reduced by 43%. Saline or AngII (1,000 ng/kg/min) was infused by subcutaneous osmotic pumps for 28 days into 12 - 14 week-old male Cre0/0 and 1/0 mice. As expected, systolic blood pressure increased similarly in both AngII-infused Cre 0/0 and 1/0 mice compared to saline-infused mice. Aortic rupture occurred within 3 to 10 days after AngII infusion in 17% of AngII-infused Cre 0/0 mice, while LRP1 deletion in Cre 1/0 mice increased aortic rupture to 27%. Aortic diameter in the survivors was significantly increased in Cre1/0 mice compared to Cre0/0 mice. Histologically, elastin fragmentation was detected in the aorta of AngII-infused Cre 0/0 mice and greater in Cre1/0 mice. Conclusion: LRP1 in second heart field-derived SMCs of the outer media may play a critical role in the pathogenesis of TAA.