Background: Peroxisome proliferator-activated receptors (PPARs) form a subfamily of the nuclear receptor superfamily and three isoforms, PPAR- 慣, -款, -灌, have been identified thus far. Because of its ubiquitous expression and the paucity of selective ligands, PPAR-灌 is the least understood PPAR subtype. Although recent data implicate PPAR-款 activation in EPC regulation, the effect of PPAR-灌 activation on EPC has not been evaluated yet. Methods and Results: Human EPCs were cultured under the variable concentration of GW501516 (10nM, 50nM, 100nM), potent and highly selective PPAR-灌 agonist. In trypan blue exclusion assays, PPAR-灌 activation significantly enhanced EPC proliferation, and inhibited apoptosis dose dependently. The latter was confirmed again by apoptosis FACS. In cell cycle FACS, the proportion of EPCs in S-phase is increased twofold under 100nM GW501516 against vehicle-treated EPCs. (p<0.05) On co-culture with human gastroepiploic artery endothelial cells (GEAEC), pretreated EPCs showed more matrigel tubule formation according as GW501516 concentration rises. In Boyden chamber experiments, EPCs migration increased in proportion to GW501516 concentration. In ELISA using supernatant, PPAR-灌 activation induced more VEGF secretion by EPCs. And to verify in vivo effects of PPAR-灌 activation, nude mouse hindlimb ischemia model was used. GW501516-pretreated and non-pretreated EPCs were injected (2X105/mouse) into systemic arterial circulation through left ventricular cavity. GW501516-pretreated EPCs significantly improved blood flow recovery and prevented limb loss compared with non-pretreated EPCs (n=51, p<0.05). Conclusions: PPAR-灌 activation enhances EPCs proliferation, function, and inhibits apoptosis from nutrient deprived stress. Furthermore PPAR-灌 pretreatment significantly increased EPCs capacity to induce neovascularization in vivo. We expect that PPAR-灌 ligands may be used for therapeutic purpose in cardiovascular disease including ischemic heart disease.