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Identification of vasodilator‐stimulated phosphoprotein (VASP) as an HIF‐regulated tissue permeability factor during hypoxia
Author(s) -
Rosenberger Peter,
Khoury Joseph,
Kong Tianqing,
Weissmüller Thomas,
Robinson Andreas M.,
Colgan Sean P.
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/fj.06-8004com
Subject(s) - psychological repression , microbiology and biotechnology , hypoxia (environmental) , hif1a , biology , chromatin immunoprecipitation , phosphoprotein , chemistry , angiogenesis , cancer research , promoter , biochemistry , phosphorylation , gene , gene expression , organic chemistry , oxygen
Increased tissue permeability is commonly associated with hypoxia of many origins. Since hypoxia‐inducible factor (HIF) represents a predominant hypoxia signaling mechanism, we compared hyp‐oxia‐elicited changes in tissue barrier function in mice conditionally lacking intestinal epithelial hypoxia‐inducible factor‐1α (hifla). Somewhat surprisingly, these studies revealed that mutant hifla mice were protected from hypoxia‐induced increases in intestinal permeability in vivo. Guided by microarray analysis of tissues derived from these mutant hifla mice, we identified HIF‐1‐dependent repression of vasodilator‐stimulated phosphoprotein (VASP), a molecule known to be important in the control of cytoskeletal dynamics, including barrier function. Studies at the mRNA and protein level confirmed hypoxia‐elicited repression of VASP in murine tissue, cultured epithelia and endothelia, as well as human saphenous vein ex vivo. Targeted repression of VASP by siRNA recapitulated our findings with hypoxia and directed overexpression of VASP abolished hypoxia‐induced barrier dysfunction. Studies in the cloned human VASP promoter revealed hypoxia‐dependent transcriptional repression, and functional studies by chromatin immunoprecipitation (ChIP) and site‐directed mutagenesis revealed hypoxia‐dependent binding of HIF‐1α to the human VASP promoter. These studies identify HIF‐1‐dependent repression of VASP as a control point for hypoxia‐regulated barrier dysfunction.—Rosenberger, P., Khoury, J., Kong, T., Weissmuller, T., Robinson, A. M., Colgan, S. P. Identification of vasodilator‐stimulated phosphoprotein (VASP) as an HIF‐regulated tissue permeability factor during hypoxia. FASEB J. 21, 2613–2621 (2007)