Physiologically low oxygen concentrations determined in fetal skin regulate hypoxia‐inducible factor 1 and transforming growth factor β3

ABSTRACT In the first‐trimester mammalian fetus, skin wounds heal with perfect reconstitution of the dermal architecture without scar formation. Understanding environmental molecular regulation in fetal wound healing may reveal scar‐limiting therapeutical strategies for the prevention of postnatal scarring wound repair. Therefore, we performed studies on fetal skin oxygenation and skin and wound expression of hypoxia‐inducible factor 1α (HIF‐1α) in the sheep model in vivo and performed studies on the potential relevance of HIF‐1α during wound healing in vitro. Skin oxygen partial pressure levels were hypoxic throughout normal development. In nonscarring fetal skin at gestation day (GD)60, HIF‐1 α could be detected neither in healthy nor in wounded tissue. At GD100, in wounds with minimal scar formation, HIF‐1 α was expressed in fibroblasts and was markedly up‐regulated at the wound edge. In scarring fetal wounds at GD120, HIF‐1 α was predominantly expressed in inflammatory cells. Expression of transforming growth factor β3 (TGF‐β3), a potent antiscarring cytokine, overlapped with HIF‐1 α expression at GD100. HIF‐1 α‐deficient mouse embryonic fibroblasts showed impaired migratory capabilities and demonstrated that TGF‐β3, but not proscarring TGF‐β1, manifests hypoxia‐ and HIF‐1α‐dependent regulation. In conclusion, HIF‐1‐dependent regulation of a potent antiscarring cytokine may provide new strategies for antiscarring manipulation of wound healing.