LRP1 (Low-Density Lipoprotein Receptor-Related Protein 1) Regulates Smooth Muscle Contractility by Modulating Ca 2+ Signaling and Expression of Cytoskeleton-Related Proteins

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Actin Cytoskeleton / drug effects
  • Actin Cytoskeleton / genetics
  • Actin Cytoskeleton / metabolism*
  • Actin Cytoskeleton / ultrastructure
  • Animals
  • Aorta / metabolism
  • Calcium Channels / genetics
  • Calcium Channels / metabolism
  • Calcium Signaling* / drug effects
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • Female
  • Gene Expression Regulation
  • Male
  • Mice, Knockout
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / metabolism*
  • Muscle, Smooth, Vascular / ultrastructure
  • Receptors, LDL / deficiency
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism*
  • Ryanodine Receptor Calcium Release Channel / genetics
  • Ryanodine Receptor Calcium Release Channel / metabolism
  • Tissue Culture Techniques
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Vasoconstriction* / drug effects
  • Vasoconstrictor Agents / pharmacology

Substances

  • CACNA2D1 protein, mouse
  • Calcium Channels
  • Cytoskeletal Proteins
  • Lrp1 protein, mouse
  • Receptors, LDL
  • Ryanodine Receptor Calcium Release Channel
  • Tumor Suppressor Proteins
  • Vasoconstrictor Agents