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Differential role of β‐catenin in VEGF and histamine‐induced MMP‐2 production in microvascular endothelial cells
Author(s) -
Doyle Jennifer L.,
Haas Tara L.
Publication year - 2009
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.22123
Subject(s) - histamine , vascular endothelial growth factor , angiogenesis , microbiology and biotechnology , vascular endothelial growth factor a , endothelial stem cell , biology , chemistry , medicine , endocrinology , cancer research , biochemistry , vegf receptors , in vitro
Increases in endothelial cell permeability and production of matrix‐degrading enzymes are two early steps in the angiogenic process. Factors such as vascular endothelial growth factor (VEGF) and histamine induce the angiogenic process through alterations in both permeability and proteolysis. We hypothesized that β‐catenin acts as a positive regulator of MMP‐2 and MT1‐MMP transcription following VEGF or histamine stimulation. Rat microvascular endothelial cells were exposed to VEGF or histamine overnight and MMP‐2 protein production was assessed by gelatin zymography. Latent MMP‐2 protein levels were increased following VEGF and histamine treatment as were MMP‐2 mRNA transcript levels. Endothelial cells exposed to VEGF and histamine had an increased level of nuclear β‐catenin, which was sensitive to inhibition of the PI3‐kinase signaling pathway. Promoter assays indicated increased transcriptional activity of both MMP‐2 and MT1‐MMP in endothelial cells co‐transfected with luciferase reporter constructs and β‐catenin. Inhibition of β‐catenin signaling with inhibitor of catenin and T cell factor (ICAT) revealed that the VEGF‐induced increase in MMP‐2 mRNA is β‐catenin dependent. Interestingly, while MMP‐2 mRNA levels increased in response to histamine H1 or H2 receptor activation, significantly larger increases were observed in cells co‐treated with ICAT and histamine or the histamine receptor agonists, HTMT and dimaprit. While both VEGF and histamine increase nuclear β‐catenin and MMP‐2 production, the role of β‐catenin in MMP‐2 regulation differs between the two stimuli. J. Cell. Biochem. 107: 272–283, 2009. © 2009 Wiley‐Liss, Inc.