title: The Role of Hypoxia-Inducible Factor in Wound Healing.
abstract: Significance:Poor wound healing remains a significant health issue for a large number of patients in the United States. The physiologic response to local wound hypoxia plays a critical role in determining the success of the normal healing process. Hypoxia-inducible factor-1 (HIF-1), as the master regulator of oxygen homeostasis, is an important determinant of healing outcomes. HIF-1 contributes to all stages of wound healing through its role in cell migration, cell survival under hypoxic conditions, cell division, growth factor release, and matrix synthesis throughout the healing process.Recent Advances:Positive regulators of HIF-1, such as prolyl-4-hydroxylase inhibitors, have been shown to be beneficial in enhancing diabetic ischemic wound closure and are currently undergoing clinical trials for treatment of several human-ischemia-based conditions.Critical Issues:HIF-1 deficiency and subsequent failure to respond to hypoxic stimuli leads to chronic hypoxia, which has been shown to contribute to the formation of nonhealing ulcers. In contrast, overexpression of HIF-1 has been implicated in fibrotic disease through its role in increasing myofibroblast differentiation leading to excessive matrix production and deposition. Both positive and negative regulators of HIF-1 therefore provide important therapeutic targets that can be used to manipulate HIF-1 expression where an excess or deficiency in HIF-1 is known to correlate with pathogenesis.Future Directions:Targeting HIF-1 during wound healing has many important clinical implications for tissue repair. Counteracting the detrimental effects of excessive or deficient HIF-1 signaling by modulating HIF-1 expression may improve future management of poorly healing wounds.
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine , Stanford, California. ; Department of Radiology, Stanford University School of Medicine , Stanford, California. ; University of Central Florida College of Medicine , Orlando, Florida.
authors.forename: Wan Xing
authors.initials: WX
authors.lastname: Hong
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine , Stanford, California. ; Department of Surgery, John A. Burns School of Medicine, University of Hawai'i , Honolulu, Hawai'i.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Hu
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine , Stanford, California.
authors.forename: Mikaela
authors.initials: M
authors.lastname: Esquivel
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine , Stanford, California.
authors.forename: Grace Y
authors.initials: GY
authors.lastname: Liang
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine , Stanford, California.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Rennert
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine , Stanford, California.
authors.forename: Adrian
authors.initials: A
authors.lastname: McArdle
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine , Stanford, California.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Paik
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine , Stanford, California.
authors.forename: Dominik
authors.initials: D
authors.lastname: Duscher
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine , Stanford, California.
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Gurtner
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine , Stanford, California.
authors.forename: H Peter
authors.initials: HP
authors.lastname: Lorenz
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine , Stanford, California.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Longaker