TY - JOUR
T1 - LRP1 protects against excessive superior mesenteric artery remodeling by modulating angiotensin II–mediated signaling
AU - Zhang, Jackie M.
AU - Au, Dianaly T.
AU - Sawada, Hisashi
AU - Franklin, Michael K.
AU - Moorleghen, Jessica J.
AU - Howatt, Deborah A.
AU - Wang, Pengjun
AU - Aicher, Brittany O.
AU - Hampton, Brian
AU - Migliorini, Mary
AU - Ni, Fenge
AU - Mullick, Adam E.
AU - Wani, Mashhood M.
AU - Ucuzian, Areck A.
AU - Lu, Hong S.
AU - Muratoglu, Selen C.
AU - Daugherty, Alan
AU - Strickland, Dudley K.
N1 - 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.
PY - 2023/1/24
Y1 - 2023/1/24
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.164751
DO - 10.1172/jci.insight.164751
M3 - Article
C2 - 36472907
AN - SCOPUS:85147046888
VL - 8
JO - JCI insight
JF - JCI insight
IS - 2
M1 - e164751
ER -