Abstract 13743: Critical Role of Endogenous Vascular Hydrogen Peroxide in Post-Ischemic Neovascularization: Studies Using Tie2-driven Endothelial Specific Catalase Transgenic Mice
Reactive oxygen species (ROS) play an important role in angiogenesis in vitro and in vivo. However, little is known about the role of endogenous vascular hydrogen peroxide (H2O2) in postnatal neovascularization, which is dependent on angiogenesis and arteriogenesis. To address this question, we used Tie2-driven endothelial specific catalase transgenic mice (Cat-Tg mice) and hindlimb ischemia model. Here we show that Cat-Tg mice exhibits significant reduction in the blood flow recovery (48%) and capillary formation (35%) with larger extent of tissue damage in the ischemic lower limb after femoral artery ligation, as compared to wild type (WT) littermates. Cat-Tg mice also show impaired ischemia-induced arteriogenesis, as determined by positive collateral remodeling in the upper limb (48%). In the early stage of ischemia-induced angiogenesis, Cat-Tg mice show a disorganized microvasculature of varying size and irregular shape without significant difference in the number of nascent vessels, suggesting the impaired vessel maturation. Furthermore, Cat-Tg show a decrease in myeloid cell recruitment, an important step for the maturation of the activated endothelium, especially at perivascular area in the upper limb (60%) and at neoangiogenic niche in the lower limb (45%). Mechanistically, Cat-Tg show significant decrease in expression of redox-sensitive adhesion molecules including VCAM-1 and MCP-1 (51% and 58%, respectively), which is required for inflammatory cell recruitment to the activated endothelial cells, in ischemic tissue. Moreover, redox-sensitive kinase p-Akt (51%), which phosphorylates eNOS, and total eNOS expression (60%) are significantly decreased in ischemic tissue in Cat-Tg mice. By contrast, phosphorylation of MAP kinases including p38 MAPK and ERK1/2 are similarly increased in both Cat-Tg and WT mice. In summary, endogenous H2O2 plays a critical role in reparative neovascularization in response to ischemia by upregulating adhesion molecules and increasing redox-sensitive kinase Akt and eNOS expression in endothelial cells in ischemic tissues. Thus, redox-regulation in endothelial cells is a potential therapeutic strategy for angiogenesis-dependent cardiovascular diseases.
- © 2011 by American Heart Association, Inc.