LRP1 (low-density lipoprotein receptor-related protein 1) regulates smooth muscle contractility by modulating Ca2+ signaling and expression of cytoskeleton-related proteins

Dianaly T. Au, Zhekang Ying, Erick O. Hernández-Ochoa, William E. Fondrie, Brian Hampton, Mary Migliorini, Rebeca Galisteo, Martin F. Schneider, Alan Daugherty, Debra L. Rateri, Dudley K. Strickland, Selen C. Muratoglu

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

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. Visual Overview-An online visual overview is available for this article.

Original languageEnglish
Pages (from-to)2651-2664
Number of pages14
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume38
Issue number11
DOIs
StatePublished - 2018

Bibliographical note

Publisher Copyright:
© 2018 American Heart Association, Inc.

Keywords

  • Aneurysm
  • Aortic aneurysm
  • Calcium signaling
  • Mutation
  • Myocytes
  • Smooth muscle

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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