2017 Cardiovascular Research Day Abstract Book

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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.
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