Abstract 18958: Apelin Signaling, a Novel Cardiac Specific Regulatory Pathway in Progenitor Cell Trafficking after Myocardial Infarction in Mice
The molecular mechanisms that govern vessel formation following ischemia remain incompletely understood. We identified Angiotensin receptor 2-like 1 (Agtrl1) as a potent molecular regulator of embryonic or postnatal neovascularization. In adult mice, the Agtrl1 receptor was highly expressed in circulatory cKit+/Flk1+ progenitor cells. Remarkably, this Agtrl1-positive population is only increased in the circulation and infarcted heart after myocardial ischemia, but failed to be recruited after hind limb ischemia, suggesting that this population is specifically involved in myocardial ischemia. Apelin, the endogenous ligand of Agtrl1, was upregulated early in the infarct region of the left ventricle (P<0.01). Also intravenous injection of apelin enhanced the recruitment cKit+/Flk1+ cells to the circulation, whereas injection of apelin into the ischemic heart resulted in increased homing of this specific cell population into the myocardium (P<0.01). This resulted in enhanced neovascularization, and subsequently diminished myocardial scar formation, improved cardiac function and reduced heart failure (P<0.05). Agtrl1-silenced BM-derived cells failed to show recruitment of cKit+/Flk1+ cells upon myocardial ischemia, resulting in diminished capillary density in the myocardium, increased scar formation and poor residual cardiac function (P<0.05). Injection of apelin into the ischemic left ventricle of these Agtrl1-silenced mice did not improve neovascularization and subsequent myocardial repair, which would suggest that the cardioprotective effect of apelin is mediated specifically by the recruitment of Agtrl1+ progenitor cells. Recruitment of Agtrl1+ progenitors cells was associated with an increase in VEGFa that was accompanied by a switch in the angiopoietin-2/angiopoietin-1 ratio in favor of angiopoietin-2. These findings indicate, for the first time, that apelin in response to myocardial ischemia could function as a specific chemoattractant for Agtrl1+/cKit+/Flk1+ progenitor cells, stimulating migration into the infarcted area, and subsequently promote neovascularization and preservation of myocardial viability and function.
- © 2010 by American Heart Association, Inc.