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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 4

Proteomic analyses reveal activation of AngII signaling pathways in SMAs of smLRP1–/– mice.

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Proteomic analyses reveal activation of AngII signaling pathways in SMAs...
(A) Principal component analysis of the LRP1+/+ (n = 5) versus smLRP1–/– (KO) (n = 4) samples from 14-week-old mice. (B) Volcano plot showing –log10 FDR (y axis) versus log2 fold-change (FC) for each protein (orange, FDR < 0.01, FC > |2|; gray, FDR > 0.01). (C) Intensity levels for LRP1 in LRP1+/+ and smLRP1–/– mice. (D) Gene ontology enrichment analysis for upregulated (left panel) or downregulated (right panel) pathways. (E) Log2 fold-change for selected LRP1 ligands as determined by mass spectral intensities. (F) Activation z scores for selected pathways and (G) P values of overlap for pathways identified in IPA software. (H) Fold-changes in myocardin-regulated proteins in smLRP1–/– mice relative to LRP1+/+ as quantified by mass spectrometry.

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

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