title: Critical role of endothelial hydrogen peroxide in post-ischemic neovascularization.
abstract: BACKGROUND
  Reactive oxygen species (ROS) play an important role in angiogenesis in endothelial cells (ECs) in vitro and neovascularization in vivo. However, little is known about the role of endogenous vascular hydrogen peroxide (H2O2) in postnatal neovascularization.
  
  
  RESULTS
  We used Tie2-driven endothelial specific catalase transgenic mice (Cat-Tg mice) and hindlimb ischemia model to address the role of endogenous H2O2 in ECs in post-ischemic neovascularization in vivo. Here we show that Cat-Tg mice exhibit significant reduction in intracellular H2O2 in ECs, blood flow recovery, capillary formation, collateral remodeling with larger extent of tissue damage after hindlimb ischemia, as compared to wild-type (WT) littermates. In the early stage of ischemia-induced angiogenesis, Cat-Tg mice show a morphologically disorganized microvasculature. Vascular sprouting and tube elongation are significantly impaired in isolated aorta from Cat-Tg mice. Furthermore, Cat-Tg mice show a decrease in myeloid cell recruitment after hindlimb ischemia. Mechanistically, Cat-Tg mice show significant decrease in eNOS phosphorylation at Ser1177 as well as expression of redox-sensitive vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemotactic protein-1 (MCP-1) in ischemic muscles, which is required for inflammatory cell recruitment to the ischemic tissues. We also observed impaired endothelium-dependent relaxation in resistant vessels from Cat-Tg mice.
  
  
  CONCLUSIONS
  Endogenous ECs-derived H2O2 plays a critical role in reparative neovascularization in response to ischemia by upregulating adhesion molecules and activating eNOS in ECs. Redox-regulation in ECs is a potential therapeutic strategy for angiogenesis-dependent cardiovascular diseases.
authors.affiliation: Department of Pharmacology, Center for Lung and Vascular Biology, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Norifumi
authors.initials: N
authors.lastname: Urao
authors.forename: Varadarajan
authors.initials: V
authors.lastname: Sudhahar
authors.forename: Seok-Jo
authors.initials: SJ
authors.lastname: Kim
authors.forename: Gin-Fu
authors.initials: GF
authors.lastname: Chen
authors.forename: Ronald D
authors.initials: RD
authors.lastname: McKinney
authors.forename: Georg
authors.initials: G
authors.lastname: Kojda
authors.forename: Tohru
authors.initials: T
authors.lastname: Fukai
authors.forename: Masuko
authors.initials: M
authors.lastname: Ushio-Fukai
mesh_terms: D000818:Animals; D002374:Catalase / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007511:Ischemia / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D008833:Microcirculation; D016328:NF-kappa B / Q000378:metabolism; D018919:Neovascularization, Physiologic; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation; D017382:Reactive Oxygen Species; D042787:Receptor, TIE-2 / Q000235:genetics; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D019010:Vascular Cell Adhesion Molecule-1; D006861:Hydrogen Peroxide; D002374:Catalase; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D042787:Receptor, TIE-2; C079086:Tek protein, mouse