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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 2

Remodeling of the SMAs in smLRP1–/– mice.

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Remodeling of the SMAs in smLRP1–/– mice.
(A and B) Representative elast...
(A and B) Representative elastin van Gieson staining of SMA sections from 16-week-old LRP1+/+ (A) or smLRP1–/– (B) mice. (C and D) Morphometric measurements of SMA medial thickness (C) and adventitial thickness (D) in 8-week-old and 25-week-old mice. (E) Lumen diameter measured from micro-CT measurements for SMA in 12-, 24-, and 64-week-old mice. (F) Lumen diameter determined from micro-CT measurements for SMA in 16-week-old male and female mice. (C, D, and F, Kruskal-Wallis nonparametric test, Dunn’s multiple-comparison test; E, 2-way ANOVA, Tukey’s post hoc test comparing LRP1+/+ and smLRP1–/– at each age.)

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

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