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.