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Arterioscler Thromb Vasc Biol. 2018 Nov;38(11):2651-2664. doi: 10.1161/ATVBAHA.118.311197.

LRP1 (Low-Density Lipoprotein Receptor-Related Protein 1) Regulates Smooth Muscle Contractility by Modulating Ca2+ Signaling and Expression of Cytoskeleton-Related Proteins.

Author information

1
From the Center for Vascular and Inflammatory Diseases (D.T.A., W.E.F., B.H., M.M., R.G., D.K.S., S.C.M.), University of Maryland School of Medicine, Baltimore.
2
Division of Cardiology, Department of Medicine (Z.Y.), University of Maryland School of Medicine, Baltimore.
3
Department of Biochemistry and Molecular Biology (E.O.H.-O., M.F.S.), University of Maryland School of Medicine, Baltimore.
4
Department of Physiology, Saha Cardiovascular Research Center, University of Kentucky, Lexington (A.D., D.L.R.).
5
Department of Surgery (D.K.S.), University of Maryland School of Medicine, Baltimore.
6
Department of Physiology (D.K.S., S.C.M.), University of Maryland School of Medicine, Baltimore.

Abstract

Objective- Mutations affecting contractile-related proteins in the ECM (extracellular matrix), microfibrils, or vascular smooth muscle cells can predispose the aorta to aneurysms. We reported previously that the LRP1 (low-density lipoprotein receptor-related protein 1) maintains vessel wall integrity, and smLRP1-/- mice exhibited aortic dilatation. The current study focused on defining the mechanisms by which LRP1 regulates vessel wall function and integrity. Approach and Results- Isometric contraction assays demonstrated that vasoreactivity of LRP1-deficient aortic rings was significantly attenuated when stimulated with vasoconstrictors, including phenylephrine, thromboxane receptor agonist U-46619, increased potassium, and L-type Ca2+ channel ligand FPL-64176. Quantitative proteomics revealed proteins involved in actin polymerization and contraction were significantly downregulated in aortas of smLRP1-/- mice. However, studies with calyculin A indicated that although aortic muscle from smLRP1-/- mice can contract in response to calyculin A, a role for LRP1 in regulating the contractile machinery is not revealed. Furthermore, intracellular calcium imaging experiments identified defects in calcium release in response to a RyR (ryanodine receptor) agonist in smLRP1-/- aortic rings and cultured vascular smooth muscle cells. Conclusions- These results identify a critical role for LRP1 in modulating vascular smooth muscle cell contraction by regulating calcium signaling events that potentially protect against aneurysm development.

KEYWORDS:

aneurysm; aortic aneurysm; calcium signaling; mutation; myocytes, smooth muscle

PMID:
30354243
PMCID:
PMC6214382
[Available on 2019-11-01]
DOI:
10.1161/ATVBAHA.118.311197

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