Selective induction of integrin beta1 by hypoxia-inducible factor: implications for wound healing.
Because of localized vascular damage and increased tissue oxygen demand, wound healing occurs in a relatively hypoxic microenvironment. These features are particularly relevant to wound healing and fibrosis in chronic inflammatory conditions, such as Crohn's disease and ulcerative colitis. In these studies, we sought to identify the contribution of hypoxia to mechanisms of wound repair in a model of the intestinal submucosa. Initial studies revealed that hypoxia promotes wound healing, as modeled by an increase in intestinal fibroblast-mediated collagen gel contraction. Guided by results from transcriptional profiling, we identified the selective induction of fibroblast integrin beta1 (ITGB1) by hypoxia. Further analysis revealed that hypoxia, as well as pharmacological activators of hypoxia-inducible factor (HIF), induce fibroblast beta1 integrin mRNA, protein, and function by as much as 4-fold. Cloning and analysis of the beta1 integrin gene promoter revealed a 10 +/- 0.8-fold increase in promoter activity in response to hypoxia, and subsequent studies identified a functional DNA binding region for HIF in the ITGB1 gene promoter. Mutational analysis of the HIF binding site within the ITGB1 promoter resulted in a significant loss of ITGB1 hypoxia-inducibility. As proof of principle, studies in a murine model of colitis revealed a correlation between colitic disease severity and tissue ITGB1 expression (R(2)=0.80). Taken together, these results demonstrate that hypoxia induces fibroblast ITGB1 expression and function by transcriptional mechanisms dependent on HIF.
Keely
Simon
S
Mucosal Inflammation Program, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
Glover
Louise E
LE
MacManus
Christopher F
CF
Campbell
Eric L
EL
Scully
Melanie M
MM
Furuta
Glenn T
GT
Colgan
Sean P
SP
D000818:Animals; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000503:physiopathology; D003094:Collagen / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D051793:Hypoxia-Inducible Factor 1 / Q000502:physiology*; D019012:Integrin beta1 / Q000235:genetics*; D051379:Mice; D014945:Wound Healing / Q000502:physiology*
D051793:Hypoxia-Inducible Factor 1; D019012:Integrin beta1; D003094:Collagen