Comparison of various niches for endothelial progenitor cell therapy on ischemic myocardial repair: coexistence of host collateralization and Akt-mediated angiogenesis produces a superior microenvironment.

OBJECTIVE Comparative studies are lacking that show the effects of different microenvironments on the activity of engrafted stem cells after myocardial infarction (MI). Here, we analyzed the temporal and spatial variations of angiogenesis, collateralization, and the expression of Akt-related signals after MI to test whether the effects of endothelial progenitor cells (EPCs) were different. METHODS AND RESULTS After the induction of MI, pigs were selected that did not develop a collateral coronary circulation (R0) or developed a significant collateral coronary circulation (R2). Both sets were allocated randomly to 4 groups: phosphate-buffered saline (intramyocardial injection of phosphate-buffered saline), EPC transplantation, LY294002 (intramyocardial injection of an Akt inhibitor), and EPCs plus LY294002. Infarcted porcine hearts at different time points and under different collateralized conditions exhibited a variety of vascular microenvironments. At 14 days post-MI, angiogenesis and the expression of Akt-mediated angiogenic cytokines predominated in R2 porcine hearts. When grafted into this microenvironment, EPCs induced the greatest effects in impeding the development of heart failure, preserving left ventricular function and dimensions, and inhibiting infarct expansion. LY294002 significantly reduced these effects. CONCLUSIONS These findings suggest that the microenvironment that coexists with collateralization and Akt-mediated angiogenesis appears to be more beneficial to cardiac repair induced by EPC therapy than other niches after MI.