Forkhead box A1 induces angiogenesis through activation of the S100A8/p38 MAPK axis in cutaneous wound healing

AbstractAbstractBackground The association between S100 calcium-binding protein A8 (S100A8) and angiogenesis has been reported in previous reports. This study focuses on the roles of S100A8 in the angiogenesis of human dermal microvascular endothelial cells (HDMECs) and in cutaneous wound healing in mice.Methods Candidate genes related to angiogenesis activity were screened using a GSE83582 dataset. The overexpression DNA plasmid of S100A8 was transfected into HDMECs to analyze its effect on cell proliferation, migration, and angiogenesis. Full-thickness skin wounds were induced on mice, followed by adenovirus treatments to analyze the function of gene alteration in wound healing and pathological changes. The upstream regulator of S100A8 was predicted by bioinformatics analysis and verified by luciferase and immunoprecipitation assays. The role of the forkhead box A1 (FOXA1)-S100A8 interaction in p38 MAPK activation and angiogenesis were validated by rescue experiments.Results S100A8 was identified as a gene significantly correlated with angiogenesis. The S100A8 upregulation promoted the proliferation, migration, and angiogenesis of HDMECs, and it promoted p38 MAPK phosphorylation. Treatment of SB203580, a p38 MAPK inhibitor, blocked the promoting effect of S100A8. FOXA1 was identified as an upstream factor of S100A8 promoting its transcription. FOXA1 overexpression in HDMECs increased p38 MAPK phosphorylation and enhanced the activity of cells, which were blocked by the S100A8 inhibition. Similar results were reproduced in vivo where FOXA1 overexpression accelerated whereas the S100A8 knockdown retarded the cutaneous wound healing in mice.Conclusion FOXA1 mediates the phosphorylation of p38 MAPK through transcription activation of S100A8, thereby inducing angiogenesis and promoting cutaneous wound healing.Keywords: FOXA1S100A8p38 MAPK pathwaywound healingangiogenesis Disclosure statementNo potential conflict of interest was reported by the author(s).Data availability statementThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.Additional informationFundingThis work was supported by Scientific Research Project of Hunan Provincial Department of Education [No. 19B417]; Hunan Provincial Scientific Research Program of Traditional Chinese Medicine [No. 2020084].