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

Authors

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

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.

Document Type

Article

Publication Date

1-2023

Notes/Citation Information

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

Digital Object Identifier (DOI)

https://doi.org/10.1172/jci.insight.164751

Repository Citation

Zhang, Jackie M.; Au, Dianaly T.; Sawada, Hisashi; Franklin, Michael K.; Moorleghen, Jessica J.; Howatt, Deborah A.; Wang, Pengjun; Aicher, Brittany O.; Hampton, Brian; Migliorini, Mary; Ni, Fenge; Mullick, Adam E.; Wani, Mashhood M.; Ucuzian, Areck A.; Lu, Hong S.; Muratoglu, Selen C.; Daugherty, Alan; and Strickland, Dudley K., "LRP1 protects against excessive superior mesenteric artery remodeling by modulating angiotensin II–mediated signaling" (2023). Saha Cardiovascular Research Center Faculty Publications. 89.
https://uknowledge.uky.edu/cvrc_facpub/89