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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 3

Ultrasonography reveals that the SMA diameter expands in smLRP1–/– mice at an exceptional rate when compared with WT mice.

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Ultrasonography reveals that the SMA diameter expands in smLRP1–/– mice ...
(A) Ultrasonography was performed on mice at 20, 24, 32, and 40 weeks of age. Maximal lumen diameters were measured on the captured images (2-way ANOVA with Tukey’s post hoc test comparing LRP1+/+ and smLRP1–/– mice at each age). (B) Rates of SMA growth using the 20-week measurements as baseline (mean ± SEM; n = 5 WT; n = 10 smLRP1–/–). (Data were fit to a straight line using linear regression analysis available in Prism 9.0 by GraphPad Software. Slopes were determined to be different, P = 0.01.)

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