Angiogenic Factor AGGF1-Primed Endothelial Progenitor Cells Repair Vascular Defect in Diabetic Mice

Hyperglycemia-triggered vascular abnormalities are the most serious complications of diabetes mellitus (DM). The major cause of vascular dysfunction in DM is endothelial injury and dysfunction associated with the reduced number and dysfunction of endothelial progenitor cells (EPCs). A major challenge is to identify key regulators of EPCs to restore DM-associated vascular dysfunction. Here, we show that EPCs from heterozygous knockout Aggf1 +/- mice showed impairment of proliferation, migration, angiogenesis, and transendothelial migration as in hyperglycemic mice fed with a high fat diet (HFD) or db/db mice. The number of EPCs from Aggf1 +/- mice was significantly reduced. Ex vivo , AGGF1 protein can fully reverse all damaging effects of hyperglycemia on EPCs. In vivo , transplantation of AGGF1-primed EPCs successfully restores blood flow, and blocks tissue necrosis and ambulatory impairment in HFD-induced hyperglycemic mice or db/db mice with diabetic hind-limb ischemia. Mechanistically, AGGF1 activates AKT and reduces nuclear localization of Fyn, which increases the nuclear level of Nrf2 and expression of anti-oxidative genes, and inhibits ROS generation. These results suggest that Aggf1 is required for essential function of EPCs, AGGF1 fully reverses the damaging effects of hyperglycemia on EPCs, and AGGF1-priming of EPCs is a novel treatment modality for vascular complications in DM.