Activated hypoxia-inducible factor-1α pathway modulates early events in stretch-induced skin neovascularization via stromal cell-derived factor-1 and vascular endothelial growth factor.

SummaryBackground Tissue expansion promotes skin regeneration. These responses occur only early after mechanical load and are then replaced by apoptosis-related events during stress relaxation. The mechanism modulating this transient process remains unknown. Objective To elucidate key phenomena that drive early regenerative events after tissue expansion. Methods Intraoperative tissue expansion was performed on 25 patients undergoing facial reconstruction. Paired skin biopsies were obtained from an expanded and unexpanded site from each patient. Differentially expressed genes were inspected by microarray and bioinformatic analysis, and dissected by quantitative polymerase chain reaction, Western blot and immunostaining. Paired biopsies from another nine patients undergoing cyclical expansion for 3 months were also investigated. Results A total of 124 upregulated and 282 downregulated genes were identified. Among them, the biological terms of extracellular matrix organization and blood vessel growth were most significantly enriched, as shown by Gene Ontology analysis. GeneMANIA dissection demonstrated an interactive network highlighted by the canonical hypoxia-inducible factor-1α (HIF-1α) pathway with stromal cell-derived factor-1 (SDF-1) and vascular endothelial growth factor (VEGFA) being the hub genes. Levels of the HIF-1α protein and its targets SDF-1 and VEGFA were elevated in expanded skin, and CD31 and Ki67 expression increased, indicating augmented vascularity and cell proliferation. Trafficking of CD34+CD133+ endothelial progenitor cells was enhanced in skin undergoing long-time cyclical expansion, a phenomenon that was usually modulated by the HIF-1α pathway. Conclusions The HIF-1α pathway is quickly activated and modulates early events in stretch-induced skin neovascularization. The effect may be augmented through enhanced endothelial progenitor cells recruitment into the expanded skin.