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

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.

• Authors: 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
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 38 Issue 11 Pg. 2651-2664 (11 2018) ISSN: 1524-4636 [Electronic] United States
• PMID: 30354243 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Video-Audio Media)

Chemical References

• CACNA2D1 protein, mouse
• Calcium Channels
• Cytoskeletal Proteins
• Low Density Lipoprotein Receptor-Related Protein-1
• Lrp1 protein, mouse
• Receptors, LDL
• Ryanodine Receptor Calcium Release Channel
• Tumor Suppressor Proteins
• Vasoconstrictor Agents

Topics

• Actin Cytoskeleton (drug effects, genetics, metabolism, ultrastructure)
• Animals
• Aorta (metabolism)
• Calcium Channels (genetics, metabolism)
• Calcium Signaling (drug effects)
• Cytoskeletal Proteins (genetics, metabolism)
• Female
• Gene Expression Regulation
• Low Density Lipoprotein Receptor-Related Protein-1
• Male
• Mice, Knockout
• Muscle, Smooth, Vascular (drug effects, metabolism, ultrastructure)
• Receptors, LDL (deficiency, genetics, metabolism)
• Ryanodine Receptor Calcium Release Channel (genetics, metabolism)
• Tissue Culture Techniques
• Tumor Suppressor Proteins (deficiency, genetics, metabolism)
• Vasoconstriction (drug effects)
• Vasoconstrictor Agents (pharmacology)