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

31 Scopus citations


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
Issue number11
StatePublished - 2018

Bibliographical note

Funding Information:
This work was supported by grants from the American Heart Association (15SDG24470170, S.C. Muratoglu), National Heart, Lung, and Blood Institute, National Institutes of Health (R35 HL135743, D.K. Strickland; F31 HL131293, D.T. Au; R01 HL133723, A. Daugherty); Marfan Foundation (D.K. Strickland); National Institute of Environmental Health Sciences, National Institutes of Health (R01 ES024516, Z. Ying); National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health (R37 AR055099, M.F. Schneider); and National Cancer Institute, National Institutes of Health (F31 CA213815, W.E. Fondrie). This work also utilized an electron microscopy sample preparation instrument that was purchased with funding from a National Institutes of Health Shared Instrumentation Grant (1S10RR26870-1) awarded to the University of Maryland, Baltimore.

Publisher Copyright:
© 2018 American Heart Association, Inc.


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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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