Abstract 15497: Macrophage Polarization Induced by Phd2 Haplodeficiency Prevents Ischemic Damage by Inducing Collateral Vessel Activation
Our genetic studies showed that heterozygous deficiency of PHD2 oxygen sensor promotes vessel stabilization and maturation, thus increasing oxygen supply. Thus we investigated the role of PHD2 in ischemia. Despite femoral artery ligation, PHD2+/− mice displayed nearly normal perfusion of the lower limb that prevented the ischemic damage of the muscle and preserved the running performance. We found that, in baseline conditions, collateral arteries in PHD2+/− mice were more functional, larger, and surrounded by a thicker media layer, altogether allowing the blood flow to bypass the occlusion point. Although the total number of infiltrated inflammatory cells was comparable in both genotypes, CD206+ F4/80+ M2 macrophages were twice more abundant in PHD2+/− mice. Consistently, expression level of specific arteriogenic genes, including PDGFb, HGF, TGFb, CXCR4, SDF1, Tie2 and Neuropilin-1, was significantly increased in PHD2+/− macrophages. As result, smooth muscle cells were chemoattracted 10 times more potently towards PHD2+/− than WT macrophages in vitro. In line with these data, specific deletion of one PHD2 allele in myeloid cells resulted in enhanced collateralization, thus increased muscle perfusion and prevention of tissue necrosis in ischemia. Macrophage polarization induced by PHD2 inhibition can be therefore a useful therapeutic tool for collateral artery formation.
- © 2010 by American Heart Association, Inc.