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

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.

SUBMITTER: Zhang JM

PROVIDER: S-EPMC9977308 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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

Zhang Jackie M JM Au Dianaly T DT Sawada Hisashi H Franklin Michael K MK Moorleghen Jessica J JJ Howatt Deborah A DA Wang Pengjun P Aicher Brittany O BO Hampton Brian B Migliorini Mary M Ni Fenge F Mullick Adam E AE Wani Mashhood M MM Ucuzian Areck A AA Lu Hong S HS Muratoglu Selen C SC Daugherty Alan A Strickland Dudley K DK

JCI insight 20230124 2

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 ...[more]

PMID: 36472907

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Project description:Background Agonistic autoantibodies against the angiotensin II type 1 receptor (AT1-AAs) extensively exist in patients with hypertensive diseases and have been demonstrated to play crucial roles in the pathophysiological process of vascular remodeling. However, the treatment options are limited. The large-conductance calcium-activated potassium (BK) channel is a critical regulator and potential therapeutic target of vascular tone and architecture. We have previously observed that AT1-AAs have an inhibitory effect on BK channels. However, whether BK channel dysfunction is involved in AT1-AAs-induced vascular remodeling and the therapeutic effect of BK channel opener is unclear. Methods and Results In our study, mesenteric arteries from AT1-AAs-positive rats exhibited increased wall thickness, narrowing of the arteriolar lumen, and increased collagen accumulation. Patch clamp test results showed that the voltage sensitivity of BK channel declined in mesenteric arteriolar smooth muscle cells from AT1-AAs-positive rats. Experiments with freshly isolated mesenteric arteriolar smooth muscle cells showed that AT1-AAs reduced the opening probability, open levels, open dwell time, and calcium sensitivity of BK channel. Experiments with HEK293T cells transfected with GFP-ZERO-BK α-subunit plasmids suggested a BK channel α-subunit-dependent mechanism. BK channel α-subunit deficient, namely KCNMA1-/- rats showed a phenotype of mesenteric artery remodeling. The administration of NS1619, a specific BK channel opener targeting the α-subunit, reversed the phenotypic transition and migration induced by AT1-AAs in cultured mesenteric arteriolar smooth muscle cells. Finally, perfusion of NS1619 significantly relieved the pathological effects induced by AT1-AAs in vivo. Conclusions In summary, we provide compelling evidence that BK channel α-subunit dysfunction mediates AT1-AAs-induced mesenteric artery remodeling. Preservation of BK channel activity may serve as a potential strategy for the treatment of AT1-AAs-induced maladaptive resistance artery remodeling.

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

Publications

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

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