Abstract 11779: Tie2-Expressing Macrophages Induced by PHD2 Haplodeficiency Prevents Ischemic Damage After Limb Ischemia and Myocardial Infarction by Inducing Collateral Artery Growth
We already demonstrated 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. The same was true in a mouse model of myocardial infarction. We found that, at baseline, 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. Quantitative PCR analysis of PHD2+/- peritoneal macrophage showed the mRNA level of Tie2 was significantly up-regulated together with other arteriogenic M2 genes including Arginase1, CXCR4, CCR2, HGF, PDGF-B, FIZZ, Neuropilin1, and SDF1 when compared to WT. Smooth muscle cells (SMCs) were chemoattracted 10 times more potently towards PHD2+/- than WT macrophages in vitro, and this migration of SMCs was inhibited by combinedd silencing of SDF1 and PDGFB in PHD2+/- macrophages. Although the total number of infiltrated inflammatory cells was comparable in both genotypes, Tie2-expressing arteriogenic macrophages in adductor muscle and Tie2-expressing mononcytes in peripheral blood were 4 times more abundant in PHD2+/- mice. After conditional depletion of TEMs in bone marrow transplanted mice by using Tie2:tk-GCV system which eliminate Tie2 positive cells in bone marrow, collateral vessel number of PHD2+/- mice was decreased at the level of WT. Micro-CT and Bismuth-based angiography analysis revealed that more collateral vessels were found in the adductors or heart of PHD2+/- mice, which results in protection against ischemic damage. TEM induction by PHD2 inhibition can be therefore a useful therapeutic target for collateral artery formation in ischemic diseases.
- © 2011 by American Heart Association, Inc.