Identification of vasodilator-stimulated phosphoprotein (VASP) as an HIF-regulated tissue permeability factor during hypoxia

摘要: Increased tissue permeability is commonly associated with hypoxia of many origins. Since hypoxia-inducible factor (HIF) represents a predominant signaling mechanism, we compared hypoxia-elicited changes in barrier function mice conditionally lacking intestinal epithelial factor-1alpha (hif1a). Somewhat surprisingly, these studies revealed that mutant hif1a were protected from hypoxia-induced increases vivo. Guided by microarray analysis tissues derived mice, identified HIF-1-dependent repression vasodilator-stimulated phosphoprotein (VASP), molecule known to be important the control cytoskeletal dynamics, including function. Studies at mRNA and protein level confirmed VASP murine tissue, cultured epithelia endothelia, as well human saphenous vein ex Targeted siRNA recapitulated our findings directed overexpression abolished dysfunction. cloned promoter hypoxia-dependent transcriptional repression, functional chromatin immunoprecipitation (ChIP) site-directed mutagenesis binding HIF-1alpha promoter. These identify point for hypoxia-regulated