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

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

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish
Article numbere164751
JournalJCI insight
Volume8
Issue number2
DOIs
StatePublished - Jan 24 2023

Bibliographical note

Publisher Copyright:
© 2023, Zhang et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

ASJC Scopus subject areas

  • General Medicine

Fingerprint

Dive into the research topics of 'LRP1 protects against excessive superior mesenteric artery remodeling by modulating angiotensin II–mediated signaling'. Together they form a unique fingerprint.

Cite this