Critical Role of Endothelial Hydrogen Peroxide in Post- Ischemic Neovascularization
journal contributionposted on 2013-12-05, 00:00 authored by Norifumi Urao, Varadarajan Sudhahar, Seok-Jo Kim, Gin-Fu Chen, Ronald D. McKinney, Georg Kojda, Tohru Fukai, Masuko Ushio-Fukai
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. METHODOLOGY/PRINCIPAL FINDINGS: 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/SIGNIFICANCE: 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.
This work was supported by funds from National Institutes of Health (NIH) R01 Heart and Lung (HL)077524, HL077524-S1 (to MU-F) and HL070187 (to TF), Department of Veterans Affairs Merit Review Grant 1I01BX001232 (to TF), American Heart Association (AHA) Grant-In-Aid 0755805Z (to MU-F), AHA National Center Research Program (NCRP) Innovative Research Grant 0970336N (to MU-F) and AHA SDG grant 12SDG12060100 and AHA Post-doctoral Fellowship 09POST2250151 (to NU) and 11POST5740006 (to VS).
Publisher Statement© 2013 Urao et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The original version is available through Public Library of Science at DOI: 10.1371/journal.pone.0057618.
PublisherPublic Library of Science