Adenosine A(2A) receptor activation promotes wound neovascularization by stimulating angiogenesis and vasculogenesis.
Recent reports indicate that circulating endothelial progenitor cells (EPCs) may be recruited to sites of neovascularization where they differentiate into endothelial cells (EC). As we have previously demonstrated that adenosine A(2A) agonists promote neovascularization in wounds, we sought to determine whether adenosine A(2A) receptor agonist-augmented wound healing involves vessel sprouting (angiogenesis) or EPC recruitment (vasculogenesis) or both. Four weeks after bone marrow reconstitution from donor FVB/N Tie2GFP transgenic mice, two full-thickness excisional wounds were performed on the dorsum of FVB/N wild-type mice and treated with either an A(2A) receptor agonist (CGS-21680) or vehicle alone. Vessel density, as measured by CD31 staining, and density of EPC-derived vessels, as measured by GFP expression, were quantified in a blinded fashion using two-color fluorescence microscopy. We observed nearly a threefold increase in CD31-positive vessels and a more than 10-fold increase in GFP-positive cells in A(2A) agonist-treated 3-day old wounds, but by 6 days after wounding the differences between A(2A) agonist-treated and vehicle-treated wounds were no longer statistically significant. In conclusion, this is the first evidence that an exogenous agent such as an adenosine A(2A) receptor agonist increases neovascularization in the early stages of wound repair by increasing both EPC recruitment (vasculogenesis) and local vessel sprouting (angiogenesis).
Montesinos
M Carmen
MC
Departments of Medicine and Surgery, The Veterans Administration New York Harbor Healthcare System, New York University Cancer Institute, New York University School of Medicine, New York, New York, USA.
Shaw
Jason P
JP
Yee
Herman
H
Shamamian
Peter
P
Cronstein
Bruce N
BN
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D016025:Bone Transplantation / Q000502:physiology; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D017404:In Situ Hybridization, Fluorescence; D008164:Luminescent Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010627:Phenethylamines / Q000494:pharmacology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D058913:Purinergic Agonists; D043705:Receptor, Adenosine A2A / Q000502:physiology*; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology*; D014947:Wounds and Injuries / Q000503:physiopathology*
D008164:Luminescent Proteins; D010627:Phenethylamines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D058913:Purinergic Agonists; D043705:Receptor, Adenosine A2A; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D049452:Green Fluorescent Proteins; D000241:Adenosine