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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.

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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.
Division of Cardiology, Department of Medicine (Z.Y.), University of Maryland School of Medicine, Baltimore.
Department of Biochemistry and Molecular Biology (E.O.H.-O., M.F.S.), University of Maryland School of Medicine, Baltimore.
Department of Physiology, Saha Cardiovascular Research Center, University of Kentucky, Lexington (A.D., D.L.R.).
Department of Surgery (D.K.S.), University of Maryland School of Medicine, Baltimore.
Department of Physiology (D.K.S., S.C.M.), University of Maryland School of Medicine, Baltimore.


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.


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

[Available on 2019-11-01]

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