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2017 Cardiovascular Research Day Abstract Book

27 LRP1 Deletion in

27 LRP1 Deletion in Smooth Muscle Cells of the Outer Aortic Media Promotes Angiotensin IIinduced Thoracic Aortic Aneurysm Hisashi Sawada, MD, PhD 1 • Debra Rateri 1 • Mark Majesky, PhD 2 • Alan Daugherty, PhD 1 1Saha CVRC, University of Kentucky • 2 Center for Cardiovascular Biology, University of Washington Postdoc 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. 43

28 Sexual Dimorphism of Angiotensin II-induced Thoracic Aortic Rupture in Mice with LRP1 Deficient Second Heart Field–derived Smooth Muscle Cells Bradley Wright 1 • Hisashi Sawada, MD, PhD 1 • Jessica Moorleghen 1 • Richard Charnigo, PhD 2 • Debra Rateri 1 • Mark Majesky, PhD 3 • Alan Daugherty, PhD 1 1Saha CVRC, University of Kentucky • 2 Biostatistics, University of Kentucky • 3 Division of Cardiology, University of Washington Undergraduate Objective: Low-density lipoprotein receptor-related protein 1 (LRP1) maintains vascular homeostasis. Deletion of LRP1 in smooth muscle cells (SMCs) accelerates angiotensin II (AngII)- induced thoracic rupture and ascending aortic aneurysm. We demonstrated recently that SMCs in the outer medial layers of the ascending aorta were derived from second heart field (SHF). Deletion of LRP1 from SHF-SMCs significantly increased thoracic aortic rupture and aneurysms in male mice. The aim of this study was to determine if female sex influenced AngII-induced rupture and aneurysm in LRP1 deficient SHF-SMC mice. Methods and Results: Female LRP1 flox/flox mice were bred to male Mef2c-Cre 1/0 mice to generate study mice. Either saline or AngII (1,000 ng/kg/min) was infused by subcutaneous osmotic pumps for 28 days into 12-14 week old Cre 0/0 and Cre 1/0 mice of both sexes (N=12-31). As expected, AngII infusion increased systolic blood pressure in both sexes. During AngII infusion, aortic rupture occurred within 3 to10 days in 17% of Cre 0/0 mice, while LRP1 deletion in Cre 1/0 mice increased significantly to 27% in males. Aortic rupture rate in AngII-infused female mice was decreased significantly compared to male mice, as there were none in Cre 0/0 and within 6-14 days only 9% in Cre 1/0 female mice. Ultrasonography was used to measure ascending aortic dilation as an index of thoracic aneurysm. Ascending aortic diameter in the survivors was significantly increased in AngII-infused Cre 1/0 vs Cre 0/0 and saline-infused controls in both sexes. Conclusion: Although male and female Cre1/0 mice experienced similar dilation of the ascending aorta under AngII infusion, female Cre1/0 mice experienced a significantly increased rate of survival compared to male litter mates. Future studies will determine the mechanism of sexual dimorphism that reduces AngII-induced thoracic aortic rupture in females. 44

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