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

Fetal skin wounds heal scarlessly while adult wounds scar. Fetal wound heal ing 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 v ascular endothelial growth factor (VEGF), and transforming growth factor-be ta (TGF-beta), a potentially HIF-1-regulated scarring cytokine, on fetal an d adult responses to wounding. Incisional skin wounds were created in four sheep fetuses (twins served as controls) and two ewes at 100 days of gestat ion (term = 150 days). Fetal and adult wounds as well as non-wounded contro l tissues were harvested 2 days post-wounding. Intraoperative arterial bloo d gas analyses and invasive subcutaneous pO(2) measurements revealed that t he fetuses were indeed hypoxic while the mothers were normoxic. Expression patterns of HIF-1 alpha were investigated by Western blot analyses. HIF-1 a lpha expression in fetal wounds and fetal control skin was similar, whereas HIF-1 alpha was only detected in adult wounds but not in adult control ski n. Exposure of cultured fetal and adult dermal fibroblasts to hypoxia(1% O- 2) showed a marked induction of VEGF mRNA. In contrast, exposure of these c ell types to hypoxia did not significantly affect TGF-beta 1 mRNA expressio n in comparison to their normoxic controls. The presence of HIF-1 alpha. in fetal but not in adult normal skin indicates that HIF-1 alpha might be inv olved in fetal skin development. Conversely, the upregulation of HIF-1 alph a in adult but not early fetal wound repair might represent a pathway in th e pathogenesis of scarring, since several growth factors overexpressed in, and associated, with scarring are hypoxia-inducible. Further studies need t o be performed in order to identify hypoxia-regulated HIF-1 alpha target ge nes involved in the pathogenesis of scarring.