Critical Role of Endothelial Hydrogen Peroxide in Post-Ischemic Neovascularization

Norifumi Urao, Varadarajan Sudhahar, Seok Jo Kim, Gin Fu Chen, Ronald D. McKinney, Georg Kojda, Tohru Fukai, Masuko Ushio-Fukai*

*Corresponding author for this work

Research output: Contribution to journalArticle

27 Citations (Scopus)

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. 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.

Original languageEnglish (US)
Article numbere57618
JournalPloS one
Volume8
Issue number3
DOIs
StatePublished - Mar 5 2013

Fingerprint

angiogenesis
Endothelial cells
Catalase
Hydrogen Peroxide
Transgenic Mice
hydrogen peroxide
catalase
endothelial cells
ischemia
genetically modified organisms
Endothelial Cells
Ischemia
mice
Hindlimb
blood vessels
Oxidation-Reduction
Blood Vessels
Tissue
Phosphorylation
Vascular Cell Adhesion Molecule-1

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Urao, N., Sudhahar, V., Kim, S. J., Chen, G. F., McKinney, R. D., Kojda, G., ... Ushio-Fukai, M. (2013). Critical Role of Endothelial Hydrogen Peroxide in Post-Ischemic Neovascularization. PloS one, 8(3), [e57618]. https://doi.org/10.1371/journal.pone.0057618
Urao, Norifumi ; Sudhahar, Varadarajan ; Kim, Seok Jo ; Chen, Gin Fu ; McKinney, Ronald D. ; Kojda, Georg ; Fukai, Tohru ; Ushio-Fukai, Masuko. / Critical Role of Endothelial Hydrogen Peroxide in Post-Ischemic Neovascularization. In: PloS one. 2013 ; Vol. 8, No. 3.
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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. 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.",
author = "Norifumi Urao and Varadarajan Sudhahar and Kim, {Seok Jo} and Chen, {Gin Fu} and McKinney, {Ronald D.} and Georg Kojda and Tohru Fukai and Masuko Ushio-Fukai",
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Urao, N, Sudhahar, V, Kim, SJ, Chen, GF, McKinney, RD, Kojda, G, Fukai, T & Ushio-Fukai, M 2013, 'Critical Role of Endothelial Hydrogen Peroxide in Post-Ischemic Neovascularization', PloS one, vol. 8, no. 3, e57618. https://doi.org/10.1371/journal.pone.0057618

Critical Role of Endothelial Hydrogen Peroxide in Post-Ischemic Neovascularization. / Urao, Norifumi; Sudhahar, Varadarajan; Kim, Seok Jo; Chen, Gin Fu; McKinney, Ronald D.; Kojda, Georg; Fukai, Tohru; Ushio-Fukai, Masuko.

In: PloS one, Vol. 8, No. 3, e57618, 05.03.2013.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Critical Role of Endothelial Hydrogen Peroxide in Post-Ischemic Neovascularization

AU - Urao, Norifumi

AU - Sudhahar, Varadarajan

AU - Kim, Seok Jo

AU - Chen, Gin Fu

AU - McKinney, Ronald D.

AU - Kojda, Georg

AU - Fukai, Tohru

AU - Ushio-Fukai, Masuko

PY - 2013/3/5

Y1 - 2013/3/5

N2 - 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.

AB - 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.

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