| [PMID]: | 28686658 |
| [Au] Autor: | Ciarlillo D; Celeste C; Carmeliet P; Boerboom D; Theoret C |
| [Ad] Endereço: | Département de biomédecine vétérinaire, Faculté de médecine vétérinaire, Université de Montréal, St-Hyacinthe, Québec, Canada. |
| [Ti] Título: | A hypoxia response element in the Vegfa promoter is required for basal Vegfa expression in skin and for optimal granulation tissue formation during wound healing in mice. |
| [So] Source: | PLoS One;12(7):e0180586, 2017. |
| [Is] ISSN: | 1932-6203 |
| [Cp] País de publicação: | United States |
| [La] Idioma: | eng |
| [Ab] Resumo: | Hypoxia in skin wounds is thought to contribute to healing through the induction of hypoxia inducible factor-1 (HIF-1). Although HIF-1 can regulate the expression of vascular endothelial growth factor A (Vegfa), whether hypoxia and HIF-1 are required to induce Vegfa expression in the context of wound healing is unknown. To test this hypothesis, we evaluated Vegfa expression and wound healing in mutant mice that lack a functional HIF-1 binding site in the Vegfa promoter. Full-thickness excisional wounds were made using a biopsy punch, left to heal by second intention, and granulation tissue isolated on a time course during healing. mRNA levels of Vegfa and its target genes platelet-derived growth factors B (Pdgfb) and stromal cell-derived factor-1 (Sdf1) were measured by RT-qPCR, and HIF-1alpha and VEGFA protein levels measured by immunoblotting. Lower levels of Vegfa, Pdgf1 and Sdf1 mRNA were found in intact skin of mutant mice relative to wild-type controls (n = 6 mice/genotype), whereas levels in granulation tissue during wound healing were unaltered. VEGFA protein levels were also lower in intact skin of the mutant versus the wild-type mice. Decreased Vegfa mRNA levels in skin of mutant mice could not be attributed to decreased HIF-1alpha protein expression, and were therefore a consequence of the loss of HIF-1 responsiveness of the Vegfa promoter. Comparative histologic analyses of healing wounds in mutant and wild-type mice (n = 8 mice/genotype) revealed significant defects in granulation tissue in the mutant mice, both in terms of quantity and capillary density, although epithelialization and healing rates were unaltered. We conclude that HIF-1 is not a major regulator of Vegfa expression during wound healing; rather, it serves to maintain basal levels of expression of Vegfa and its target genes in intact skin, which are required for optimal granulation tissue formation in response to wounding. |
| [Mh] Termos MeSH primário: |
Subunidade alfa do Fator 1 Induzível por Hipóxia/genética
Pele/metabolismo
Fator A de Crescimento do Endotélio Vascular/genética
Cicatrização/genética
|
| [Mh] Termos MeSH secundário: |
Animais
Sítios de Ligação
Quimiocina CXCL12/genética
Proteínas de Ligação a DNA/genética
Modelos Animais de Doenças
Regulação da Expressão Gênica
Tecido de Granulação/metabolismo
Tecido de Granulação/fisiopatologia
Seres Humanos
Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese
Linfocinas/genética
Camundongos
Fator de Crescimento Derivado de Plaquetas/genética
Regiões Promotoras Genéticas
Elementos de Resposta/genética
Pele/fisiopatologia
Fator A de Crescimento do Endotélio Vascular/biossíntese
|
| [Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (Chemokine CXCL12); 0 (Cxcl12 protein, mouse); 0 (DNA-Binding Proteins); 0 (Hif1a protein, mouse); 0 (Hypoxia-Inducible Factor 1, alpha Subunit); 0 (Lymphokines); 0 (Pdgfd protein, mouse); 0 (Platelet-Derived Growth Factor); 0 (Vascular Endothelial Growth Factor A); 0 (vascular endothelial growth factor A, mouse) |
| [Em] Mês de entrada: | 1710 |
| [Cu] Atualização por classe: | 171006 |
[Lr] Data última revisão:
| 171006 |
| [Sb] Subgrupo de revista: | IM |
| [Da] Data de entrada para processamento: | 170708 |
| [St] Status: | MEDLINE |
| [do] DOI: | 10.1371/journal.pone.0180586 |
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