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

Peter Rosenberger^*,, Joseph Khoury^,, Tianqing Kong, Thomas Weissmüller, Andreas M. Robinson and Sean P. Colgan^,,1

^* Department of Anesthesiology and Intensive Care Medicine, Tübingen University Hospital, Tubingen, Germany;

Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA;

Department of Anesthesia and Perioperative Medicine, Childrens Hospital and Harvard Medical School, Boston, Massachusetts, USA; and

Mucosal Inflammation Program, University of Colorado Health Sciences Center, Denver, Colorado, USA

¹Correspondence: University of Colorado Health Sciences Center, Biochemistry Research Bldg., Rm. 702, 4200 E. 9th Ave, Denver, CO 80220, USA. E-mail: colgan{at}zeus.bwh.harvard.edu

Increased tissue permeability is commonly associated with hypoxia of many origins. Since hypoxia-inducible factor (HIF) represents a predominant hypoxia signaling mechanism, we compared hypoxia-elicited changes in tissue barrier function in mice conditionally lacking intestinal epithelial hypoxia-inducible factor-1 (hif1a). Somewhat surprisingly, these studies revealed that mutant hif1a mice were protected from hypoxia-induced increases in intestinal permeability in vivo. Guided by microarray analysis of tissues derived from these mutant hif1a 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-1 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., Weissmüller, T., Robinson, A. M., Colgan, S. P. Identification of vasodilator-stimulated phosphoprotein (VASP) as an HIF-regulated tissue permeability factor during hypoxia.

Key Words: barrier function • actin

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