Abstract
BackgroundReactive 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 FindingsWe 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/SignificanceEndogenous 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.
Highlights
Neovascularization in response to tissue ischemia or injury is an important adaptive mechanism that is involved in wound repair as well as ischemic heart and limb diseases
Using endothelium-specific catalase overexpressing transgenic mice [27,28], the present study provides the direct evidence that endogenous H2O2 in endothelial cells (ECs) plays a critical role in reparative neovascularization by promoting angiogenesis, collateral remodelling, and myeloid cell recruitment to ischemic tissues
We previously characterized the Cat-Tg mice driven by Tie2 promoter and demonstrated that human catalase protein is overexpressed in the endothelium, but not non-vascular cells [27]
Summary
Neovascularization in response to tissue ischemia or injury is an important adaptive mechanism that is involved in wound repair as well as ischemic heart and limb diseases It depends on angiogenesis (a process of new vessel formation from pre-existing capillary-like endothelial cells (ECs)), arteriogenesis [1] and bone marrow (BM)-derived vascular progenitor cells [2,3,4,5]. Inflammatory cell infiltration into ischemic tissues, which is in part mediated by the adhesion molecules expressed in ECs, plays an important role in ischemia-induced revascularization by releasing vascular endothelial growth factor (VEGF) [6]. Little is known about the role of endogenous vascular hydrogen peroxide (H2O2) in postnatal neovascularization
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