Hypoxia-regulated gene expression in fetal wound regeneration and adult wound repair

Abstract

 Fetal skin wounds heal scarlessly while adult wounds scar. Fetal wound healing occurs in a physiologically hypoxic environment whereas in adult wound healing, cells have to acutely adapt to hypoxia caused by locally impaired blood supply. We examined the expression of hypoxia-inducible factor 1 (HIF-1), a potent transcriptional regulator of oxygen-dependent genes such as vascular endothelial growth factor (VEGF), and transforming growth factor-β (TGF-β), a potentially HIF-1-regulated scarring cytokine, on fetal and adult responses to wounding. Incisional skin wounds were created in four sheep fetuses (twins served as controls) and two ewes at 100 days of gestation (term = 150 days). Fetal and adult wounds as well as non-wounded control tissues were harvested 2 days post-wounding. Intraoperative arterial blood gas analyses and invasive subcutaneous pO₂ measurements revealed that the fetuses were indeed hypoxic while the mothers were normoxic. Expression patterns of HIF-1α were investigated by Western blot analyses. HIF-1α expression in fetal wounds and fetal control skin was similar, whereas HIF-1α was only detected in adult wounds but not in adult control skin. Exposure of cultured fetal and adult dermal fibroblasts to hypoxia (1% O₂) showed a marked induction of VEGF mRNA. In contrast, exposure of these cell types to hypoxia did not significantly affect TGF-β1 mRNA expression in comparison to their normoxic controls. The presence of HIF-1α in fetal but not in adult normal skin indicates that HIF-1α might be involved in fetal skin development. Conversely, the upregulation of HIF-1α in adult but not early fetal wound repair might represent a pathway in the pathogenesis of scarring, since several growth factors overexpressed in, and associated, with scarring are hypoxia-inducible. Further studies need to be performed in order to identify hypoxia-regulated HIF-1α target genes involved in the pathogenesis of scarring.