Deletion of LRP1 in Smooth Muscle Cells Induces Infrarenal Aortic Aneurysms in Mice
- 1University of Kentucky
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.
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BibTeX
@misc{franklin2026deletion,
title = {{Deletion of LRP1 in Smooth Muscle Cells Induces Infrarenal Aortic Aneurysms in Mice}},
author = {M. Franklin and G. Fan and B. Li and P. Wang and D. A. Howatt and J. Moorleghen and A. E. Mullick and A. Daugherty and H. S. Lu},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.16.759442},
url = {https://www.biorxiv.org/content/10.64898/2026.10.16.759442v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Deletion of LRP1 in Smooth Muscle Cells Induces Infrarenal Aortic Aneurysms in Mice
AU - M. Franklin
AU - G. Fan
AU - B. Li
AU - P. Wang
AU - D. A. Howatt
AU - J. Moorleghen
AU - A. E. Mullick
AU - A. Daugherty
AU - H. S. Lu
PY - 2026
DA - 2026/10/16
PB - bioRxiv
DO - 10.64898/2026.10.16.759442
UR - https://www.biorxiv.org/content/10.64898/2026.10.16.759442v1
AB - 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.
ER -