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LRP1 protects against excessive superior mesenteric artery remodeling by modulating angiotensin II–mediated signaling
Jackie M. Zhang, … , Alan Daugherty, Dudley K. Strickland
Jackie M. Zhang, … , Alan Daugherty, Dudley K. Strickland
Published December 6, 2022
Citation Information: JCI Insight. 2023;8(2):e164751. https://doi.org/10.1172/jci.insight.164751.
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Research Article Vascular biology

LRP1 protects against excessive superior mesenteric artery remodeling by modulating angiotensin II–mediated signaling

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Abstract

Vascular smooth muscle cells (vSMCs) exert a critical role in sensing and maintaining vascular integrity. These cells abundantly express the low-density lipoprotein receptor–related protein 1 (LRP1), a large endocytic signaling receptor that recognizes numerous ligands, including apolipoprotein E–rich lipoproteins, proteases, and protease-inhibitor complexes. We observed the spontaneous formation of aneurysms in the superior mesenteric artery (SMA) of both male and female mice in which LRP1 was genetically deleted in vSMCs (smLRP1–/– mice). Quantitative proteomics revealed elevated abundance of several proteins in smLRP1–/– mice that are known to be induced by angiotensin II–mediated (AngII-mediated) signaling, suggesting that this pathway was dysregulated. Administration of losartan, an AngII type I receptor antagonist, or an angiotensinogen antisense oligonucleotide to reduce plasma angiotensinogen concentrations restored the normal SMA phenotype in smLRP1–/– mice and prevented aneurysm formation. Additionally, using a vascular injury model, we noted excessive vascular remodeling and neointima formation in smLRP1–/– mice that was restored by losartan administration. Together, these findings reveal that LRP1 regulates vascular integrity and remodeling of the SMA by attenuating excessive AngII-mediated signaling.

Authors

Jackie M. Zhang, Dianaly T. Au, Hisashi Sawada, Michael K. Franklin, Jessica J. Moorleghen, Deborah A. Howatt, Pengjun Wang, Brittany O. Aicher, Brian Hampton, Mary Migliorini, Fenge Ni, Adam E. Mullick, Mashhood M. Wani, Areck A. Ucuzian, Hong S. Lu, Selen C. Muratoglu, Alan Daugherty, Dudley K. Strickland

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Figure 5

Losartan administration restores the arterial phenotype of smLRP1–/– mice.

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Losartan administration restores the arterial phenotype of smLRP1–/– mic...
After weaning at 3–4 weeks of age, mice were provided with or without losartan (0.6 g/L drinking water) and kept on the drug for 12 weeks before analysis. (A–C) Elastic van Gieson (EVG) staining of sections from LRP1+/+ SMAs (A) or smLRP1–/– (B) mice or (C) smLRP1–/– mice administered with losartan. smLRP1–/– mice receiving losartan had fewer breaks in the elastic laminae (D) and reduced medial thickening (E) than those observed in smLRP1–/– mice. Micro-CT measurements of lumen diameter for male (F) and female (G) LRP1+/+ or smLRP1–/– mice with or without losartan treatments (2-way ANOVA, Tukey’s multiple-comparison test).

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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