RESUMO
Angiogenesis is a critical aspect of wound healing. We investigated the role of keratinocytes in promoting angiogenesis in mice with lineage-specific deletion of the transcription factor FOXO1. The results indicate that keratinocyte-specific deletion of Foxo1 reduces VEGFA expression in mucosal and skin wounds and leads to reduced endothelial cell proliferation, reduced angiogenesis, and impaired re-epithelialization and granulation tissue formation. In vitro FOXO1 was needed for VEGFA transcription and expression. In a porcine dermal wound-healing model that closely resembles healing in humans, local application of a FOXO1 inhibitor reduced angiogenesis. This is the first report that FOXO1 directly regulates VEGFA expression and that FOXO1 is needed for normal angiogenesis during wound healing. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Assuntos
Proteína Forkhead Box O1/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Gengiva/metabolismo , Mucosa Bucal/metabolismo , Neovascularização Fisiológica , Pele/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Cicatrização , Ferimentos e Lesões/metabolismo , Animais , Linhagem Celular , Modelos Animais de Doenças , Feminino , Proteína Forkhead Box O1/deficiência , Proteína Forkhead Box O1/genética , Fatores de Transcrição Forkhead/genética , Gengiva/lesões , Gengiva/patologia , Humanos , Queratinócitos/metabolismo , Queratinócitos/patologia , Masculino , Camundongos Knockout , Mucosa Bucal/lesões , Mucosa Bucal/patologia , Transdução de Sinais , Pele/lesões , Pele/patologia , Suínos , Porco Miniatura , Fator A de Crescimento do Endotélio Vascular/genética , Ferimentos e Lesões/genética , Ferimentos e Lesões/patologiaRESUMO
The forkhead box O1 (FOXO1) transcription factor plays a key role in wound healing process. Recently it has been reported that lineage-specific genetic ablation of FOXO1 significantly improves diabetic wound healing in a mouse model. To investigate the clinical usefulness of these findings, translational preclinical studies with a large animal model are needed. We report for the first time that the local application of a FOXO1 inhibitor (AS1842856) significantly improves connective tissue healing in a preclinical T2DM minipig model, reflected by increased collagen matrix formation, increased myofibroblast numbers, improved angiogenesis, and a shift in cell populations from pro-inflammatory (IL-1ß+, TNF-α+ and iNOS+) to pro-healing (CD163+). Our results set up the basis for the clinical application of a FOXO1 antagonist in early diabetic wounds where there is impaired connective tissue healing.