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TIMP‐2/α3β1 integrin signaling inhibits VEGF‐A‐induced vascular permeability through upregulation of cAMP and downregulation of NO‐induced cGMP synthesis
Author(s) -
LEE SEO JIN,
Seo DongWan,
Wei Beiyang,
Diaz Tere,
StetlerStevenson William G
Publication year - 2007
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.21.6.lb21-d
Subject(s) - downregulation and upregulation , microbiology and biotechnology , adherens junction , chemistry , vascular permeability , angiogenesis , phosphorylation , biology , endocrinology , cancer research , cadherin , cell , biochemistry , gene
The tissue inhibitor of metalloproteinase‐2 (TIMP‐2)‐induced α3β1 integrin signaling has been previously shown to inhibit angiogenesis via a MMP‐independent mechanism. Here, we provide evidence that TIMP‐2 also inhibits VEGF‐A‐induced vascular permeability in vitro and in vivo via an MMP‐independent process. This mechanism involves the inhibition of VEGF‐A‐stimulated phosphorylation of Tyr951, Tyr996, and Tyr1175 on the VEGF receptor‐2 by TIMP‐2. Also, TIMP‐2 dramatically induces cyclic AMP (cAMP) production via SH2‐domain‐containing protein tyrosine phosphatase‐1 (SHP‐1)‐dependent manner. TIMP‐2 restrained cGMP synthesis increased by VEGF‐A through inactivation of AKT/eNOS. These effects by TIMP‐2 result in reduced VEGF‐A‐induced vascular permeability. Furthermore, TIMP‐2 rapidly increased redistribution of VE‐cadherin into actin cytoskeleton via a SHP‐1/cAMP‐dependent mechanism. These findings have important implication for regulation of the endothelial barrier function by TIMP‐2 through the endothelial cell adherens junctions stabilization. Our findings suggest that TIMP‐2 inhibits VEGF‐A‐induced vascular permeability through cAMP upregulation, cGMP downregulation, and VE‐cadherin redistribution and confirm the pivotal role of TIMP‐2 in regulation of endothelial cell function.