Endothelial colony-forming cells (ECFCs) are recruited to the sites of ischemic injury in order to contribute to neovascularization and repair of injured tissues. However, therapeutic potential of ECFCs is limited due to low homing and engraftment efficiency of transplanted ECFCs. The
G-protein-coupled
formyl peptide receptor (FPR) 2 has been implicated in regulation of
inflammation and angiogenesis, while the role of FPR2 in homing and engraftment of ECFCs and neovascularization in ischemic tissues has not been fully defined. This study was undertaken to investigate the effects of
WKYMVm, a selective FPR2 agonist isolated by screening
synthetic peptide libraries, on homing ability of ECFCs and vascular regeneration of ischemic tissues.
WKYMVm stimulated chemotactic migration, angiogenesis, and proliferation ability of human ECFCs in vitro.
Small interfering RNA-mediated silencing of FPR2, but not FPR3, abrogated
WKYMVm-induced migration and angiogenesis of ECFCs.
Intramuscular injection of
WKYMVm resulted in attenuation of severe hind limb
ischemia and promoted neovascularization in ischemic limb. ECFCs transplanted via tail vein into nude mice were incorporated into capillary vessels in the ischemic hind limb, resulting in augmented neovascularization and improved ischemic
limb salvage.
Intramuscular injection of
WKYMVm promoted homing of exogenously administered ECFCs to the ischemic limb and ECFC-mediated vascular regeneration. Silencing of FPR2 expression in ECFCs resulted in abrogation of
WKYMVm-induced in vivo homing of exogenously transplanted ECFCs to the ischemic limb, neovascularization, and ischemic
limb salvage. These results suggest that
WKYMVm promotes repair of ischemic tissues by stimulating homing of ECFCs and neovascularization via a FPR2-dependent mechanism.