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 three-fold 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).