Endothelial G protein-coupled receptor kinase 2 regulates vascular homeostasis through the control of free radical oxygen species

Arterioscler Thromb Vasc Biol. 2013 Oct;33(10):2415-24. doi: 10.1161/ATVBAHA.113.302262. Epub 2013 Aug 15.

Abstract

Objective: The role of endothelial G protein-coupled receptor kinase 2 (GRK2) was investigated in mice with selective deletion of the kinase in the endothelium (Tie2-CRE/GRK2(fl/fl)).

Approach and results: Aortas from Tie2-CRE/GRK2(fl/fl) presented functional and structural alterations as compared with control GRK2(fl/fl) mice. In particular, vasoconstriction was blunted to different agonists, and collagen and elastic rearrangement and macrophage infiltration were observed. In primary cultured endothelial cells deficient for GRK2, mitochondrial reactive oxygen species was increased, leading to expression of cytokines. Chronic treatment with a reactive oxygen species scavenger in mice corrected the vascular phenotype by recovering vasoconstriction, structural abnormalities, and reducing macrophage infiltration.

Conclusions: These results demonstrate that GRK2 removal compromises vascular phenotype and integrity by increasing endothelial reactive oxygen species production.

Keywords: G protein-coupled receptor kinases; endothelial cells; mitochondria; vascular medicine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta, Thoracic / drug effects
  • Aorta, Thoracic / enzymology*
  • Aorta, Thoracic / pathology
  • Aorta, Thoracic / physiopathology
  • Cells, Cultured
  • Collagen / metabolism
  • Cytokines / metabolism
  • Dose-Response Relationship, Drug
  • Elastic Tissue / metabolism
  • Elastic Tissue / pathology
  • Endothelial Cells / enzymology*
  • Endothelial Cells / pathology
  • Free Radical Scavengers / pharmacology
  • G-Protein-Coupled Receptor Kinase 2 / deficiency
  • G-Protein-Coupled Receptor Kinase 2 / genetics
  • G-Protein-Coupled Receptor Kinase 2 / metabolism*
  • Homeostasis
  • Inflammation Mediators / metabolism
  • Integrases / genetics
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Mice, Knockout
  • Phenotype
  • Reactive Oxygen Species / metabolism*
  • Receptor, TIE-2 / genetics
  • Signal Transduction
  • Vasoconstriction / drug effects
  • Vasoconstrictor Agents / pharmacology

Substances

  • Cytokines
  • Free Radical Scavengers
  • Inflammation Mediators
  • Reactive Oxygen Species
  • Vasoconstrictor Agents
  • Collagen
  • Receptor, TIE-2
  • Tek protein, mouse
  • GRK2 protein, mouse
  • G-Protein-Coupled Receptor Kinase 2
  • Cre recombinase
  • Integrases