Deletion of LRP1 in Smooth Muscle Cells Induces Infrarenal Aortic Aneurysms in Mice

Abstract

Background: Low-density lipoprotein receptor-related protein 1 (LRP1) in smooth muscle cells (SMCs) is essential for maintaining aortic wall integrity. This study investigated whether deletion of LRP1 in SMCs induces region-specific aortic pathology and evaluated a potential therapeutic strategy. Methods: Lrp1-floxed mice were bred with Sm22-Cre+/0 mice to generate mice with SMC-LRP1 deletion (SMC-LRP1-/-) and wild-type littermates (SMC-LRP1+/+). Micro-computed tomography (micro-CT) was used to visualize the aorta, and aortic tissue sections were characterized histologically. To evaluate a potential therapeutic strategy, antisense oligonucleotides (ASOs) targeting hepatocyte-derived angiotensinogen (AGT) were administered to inhibit AGT synthesis. Results: Immunostaining and Western blotting confirmed LRP1 deletion in aortic SMCs. At 40 weeks of age, micro-CT revealed marked increases in aortic width and volume. Although dilatation occurred throughout the aorta, the infrarenal region exhibited the greatest expansion in both male and female SMC-LRP1-/- mice compared with SMC-LRP1+/+ littermates; subsequent analyses therefore focused on this region. LRP1 deletion in SMCs caused pronounced SMC loss and increased collagen deposition in the infrarenal aorta. Inhibition of hepatocyte-derived AGT with ASO attenuated infrarenal aortic dilatation and preserved aortic wall integrity in both male and female mice. Conclusions: Deletion of LRP1 in SMCs causes progressive aortic dilatation that includes the infrarenal aorta. Pharmacologic inhibition of hepatocyte-derived AGT attenuates infrarenal aortic dilatation.