Adenosine A₂B receptor agonism inhibits neointimal lesion development after arterial injury in apolipoprotein E-deficient mice

Arterioscler Thromb Vasc Biol. 2012 Sep;32(9):2197-205. doi: 10.1161/ATVBAHA.112.252924. Epub 2012 Jun 28.

Abstract

Objective: The A(2B) adenosine receptor (A(2B)R) is highly expressed in macrophages and vascular smooth muscle cells and has been established as an important regulator of inflammation and vascular adhesion. Recently, it has been demonstrated that A(2B)R deficiency enhances neointimal lesion formation after vascular injury. Therefore, we hypothesize that A(2B)R agonism protects against injury-induced intimal hyperplasia.

Methods and results: Apolipoprotein E-deficient mice were fed a Western-type diet for 1 week, after which the left common carotid artery was denuded. Mice were treated with the A(2B) receptor agonist BAY60-6583 or vehicle control for 18 days. Interestingly, lumen stenosis as defined by the neointima/lumen ratio was inhibited by treatment with the A(2B) receptor agonist, caused by reduced smooth muscle cell proliferation. Collagen content was significantly increased in the BAY60-6583-treated mice, whereas macrophage content remained unchanged. In vitro, vascular smooth muscle cell proliferation decreased dose dependently whereas collagen content of cultured smooth muscle cells was increased by BAY60-6583.

Conclusions: Our data show that activation of the adenosine A(2B) receptor protects against vascular injury, while it also enhances plaque stability as indicated by increased collagen content. These outcomes thus point to A(2B) receptor agonism as a new therapeutic approach in the prevention of restenosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine A2 Receptor Agonists / pharmacology*
  • Aminopyridines / pharmacology*
  • Animals
  • Apolipoproteins E / deficiency*
  • Apolipoproteins E / genetics
  • CHO Cells
  • Cardiovascular Agents / pharmacology*
  • Carotid Artery Injuries / drug therapy*
  • Carotid Artery Injuries / genetics
  • Carotid Artery Injuries / metabolism
  • Carotid Artery Injuries / pathology
  • Carotid Artery, Common / drug effects
  • Carotid Artery, Common / metabolism
  • Carotid Artery, Common / pathology
  • Carotid Stenosis / genetics
  • Carotid Stenosis / metabolism
  • Carotid Stenosis / pathology
  • Carotid Stenosis / prevention & control*
  • Cell Adhesion / drug effects
  • Cell Proliferation / drug effects
  • Collagen / metabolism
  • Cricetinae
  • Cricetulus
  • Dietary Fats
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / pathology
  • Female
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Knockout
  • Muscle, Smooth, Vascular / drug effects*
  • Muscle, Smooth, Vascular / injuries
  • Muscle, Smooth, Vascular / metabolism
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Smooth Muscle / drug effects*
  • Myocytes, Smooth Muscle / metabolism
  • Myocytes, Smooth Muscle / pathology
  • Neointima
  • Neutrophil Activation
  • Neutrophils / drug effects
  • Neutrophils / metabolism
  • Platelet Activation / drug effects
  • Receptor, Adenosine A2B / drug effects*
  • Receptor, Adenosine A2B / genetics
  • Receptor, Adenosine A2B / metabolism
  • Time Factors
  • Transfection

Substances

  • Adenosine A2 Receptor Agonists
  • Aminopyridines
  • Apolipoproteins E
  • BAY 60-6583
  • Cardiovascular Agents
  • Dietary Fats
  • Receptor, Adenosine A2B
  • Collagen