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Protein Tyrosine Phosphatase 1B Deficiency Results in Reduced ROS Production and Perivascular Macrophage Infiltration in Ischemic Tissue and Impaired Post‐ischemic Neovascularization
Author(s) -
Urao Norifumi,
Chen GinFu,
Razvi Masooma,
McKinney Ronald D,
Fukai Tohru,
UshioFukai Masuko
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1092.1
Subject(s) - angiogenesis , neovascularization , protein tyrosine phosphatase , vascular permeability , nadph oxidase , inflammation , chemistry , microbiology and biotechnology , downregulation and upregulation , biology , reactive oxygen species , immunology , cancer research , endocrinology , signal transduction , biochemistry , gene
Post‐ischemic neovascularization is mediated by inflammation, angiogenesis and reactive oxygen species (ROS) derived from NADPH oxidase (Nox). We showed that protein tyrosine phosphatase (PTP) 1B functions as a negative regulator for VEGF‐induced angiogenesis in endothelial cells (ECs). However, its role in post‐ischemic neovascularization in vivo remains unknown. Here we show that PTP1B expression and activity are increased in mouse hindlimb ischemia. PTP1B −/− (KO) mice exhibit enhanced capillary density in non‐inflammatory ischemic limb, while reduced blood flow recovery, arterioles and vessel maturation, and increased vascular permeability. Bone marrow transplantation reveals that PTP1B in non‐hematopoietic cells has a greater impact on the phenotype of KO mice. In ischemic tissues of KO mice, perivascular macrophage infiltration, VEGF induction, and ROS production are inhibited with reduced expression of redox‐sensitive adhesion molecules ICAM‐1 and VCAM‐1 as well as Nox2. In summary, PTP1B functions as a negative regulator for EC‐dependent angiogenesis but also positive regulator for ROS production through upregulating Nox2 in ischemic muscles, which increases adhesion molecules and subsequent macrophage perivascular recruitment. This result provides insight into the importance of ROS producing microenvironment in ischemic tissues for reparative neovascularization.