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Selective induction of integrin βi by hypoxia‐inducible factor: implications for wound healing
Author(s) -
Keely Simon,
Glover Louise E.,
MacManus Christopher F.,
Campbell Eric L.,
Scully Melanie M.,
Furuta Glenn T.,
Colgan Sean P.
Publication year - 2009
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.08-125344
Subject(s) - wound healing , hypoxia (environmental) , fibroblast , hypoxia inducible factors , gene expression , chemistry , microbiology and biotechnology , biology , cancer research , gene , immunology , cell culture , biochemistry , genetics , organic chemistry , oxygen
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 fibroblastmediated collagen gel contraction. Guided by results from transcriptional profiling, we identified the selective induction of fibroblast integrin β1 (ITGB1) by hypoxia. Further analysis revealed that hypoxia, as well as pharmacological activators of hypoxia‐inducible factor (HIF), induce fibroblast pi integrin mRNA, protein, and function by as much as 4‐fold. Cloning and analysis of the βi 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, S., Glover, L. E., MacManus, C. F., Campbell, E. L., Scully, M. M., Furuta, G. T., Colgan, S. P. Selective induction of integrin β1 by hypoxia‐inducible factor: implications for wound healing. FASEBJ. 23, 1338–1346 (2009)