Abstract 4938: Agtrl-1/Apelin Binding Specifically Enhances Myocardial Ischemia Driven Neovascularization and Left Ventricular Function by Attracting EPCs
The molecular mechanisms that govern the formation of new blood vessels following ischemia remain largely unknown. In order to identify new genes involved in blood vessel formation, we performed a genome-wide microarray screen using the affymetrix platform in mice and zebrafish. Gene expression profiles of isolated Flk1+ angioblasts during murine and piscine embryonic development were compared to those of Flk1− cells. Angiotensin receptor 2 like 1 (Agtrl-1) is one of the genes that was identified. In adult C57bl/6 mice Agtrl-1 is highly expressed in mature endothelial cells and was also detected in cKit+/Flk1+/Lin- cells, but not in Sca+/Flk1+/Lin- cells. Remarkably, the number of cKit+/Flk1+/Agtrl-1 cells was increased in the ischemic area after myocardial ischemia (P<0.001), but not after hind limb ischemia. Apelin protein expression, the endogenous ligand of Agtrl-1, was also augmented by 3-fold in the infarct region of the myocardium (P<0.01) and systemic infusion of Apelin increased the recruitment cKit+/Flk1+ EPCs to the circulation by two-fold (P<0.03). Injection of Apelin into the ischemic myocardium resulted in increased homing to the injection site of this specific population and a two-fold increase in neovascularization of the ischemic tissue (P<0.01), consequently improving cardiac function, left ventricular dimensions and diminished scar formation. These findings indicate for the first time, that apelin in response to myocardial ischemia could function as a specific chemoattractant for Agtrl-1+ EPCs, stimulating migration into the infarcted area and subsequently promoting neovascularisation and myocardial repair.