Abstract Body: Background: Low-density lipoprotein receptor-related protein 1 (LRP1) is an important protein in maintaining aortic structural integrity. It is abundant in smooth muscle cells (SMCs). In this study, we characterized spontaneous infrarenal abdominal aortic aneurysm in mice with SMC-specific deletion of LRP1.

Methods: Deletion of LRP1 in SMCs (SMC-LRP1-/-) was achieved by breeding Lrp1 floxed mice with SM22 Cre transgenic mice. Abdominal aortas were monitored in live animals every 4 weeks using ultrasonography. At termination, volume was measured using micro-CT, and pathological changes were characterized using histology and immunostaining.
Results: LRP1 deletion in SMCs was confirmed by immunochemistry staining and Western blotting. Dilatation of the infrarenal abdominal aortic region was detected by ultrasonography at 5 weeks of age and progressed at 8 and 12 weeks of age. Infrarenal abdominal aortic dilatations were also detected by volume measurements using micro-CT scan in mice at 40 weeks of age. Histological staining showed aortic medial remodeling, including increased elastic fiber fragmentations and fibrosis. Since activation of the renin-angiotensin system was reported as a mechanism of AAA, we injected antisense oligonucleotides (ASO) targeting angiotensinogen (AGT), the only substrate of the renin-angiotensin system, to SMC-LRP1-/- mice at 8 weeks of age. Significant attenuation of aortic dilations was detected in SMC-LRP1 -/- mice after 16 weeks of AGT ASO administration.
Conclusions: SMC-specific deletion of LRP1 induced spontaneous infrarenal abdominal aortic aneurysm progressively. AGT inhibition protected against SMC-specific LRP1 deletion-induced infrarenal abdominal aortic aneurysm.