Factor VII deficiency impairs cutaneous wound healing in mice.
Skin keratinocytes express tissue factor (TF) and are highly associated with skin wound healing. Although it has been demonstrated that perivascular TF expression in granulation tissue formed after dermal injury is downregulated during healing, studies of the mechanism of factor (F) VII, a TF ligand, in skin wound healing are lacking. We reported the use of a dermal punch model to demonstrate that low-expressing FVII mice (approximately 1% of wild type [WT]) exhibited impaired skin wound healing compared with WT controls. These low-FVII mice showed defective reepithelialization and reduced inflammatory cell infiltration at wound sites. This attenuated reepithelialization was associated with diminished expression of the transcription factor early growth response 1 (Egr-1). In vitro, Egr-1 was shown to be essential for the FVIIa-induced regulation of keratinocyte migration and inflammation. Both Egr-1 upregulation and downstream inflammatory cytokine appearance in keratinocytes depended on FVIIa/TF/protease-activated receptor 2 (PAR-2)-induced signaling and did not require subsequent generation of FXa and thrombin. The participation of Egr-1 in FVIIa-mediated regulation of keratinocyte function was confirmed by use of Egr-1-deficient mice, wherein a significant delay in skin wound healing after injury was observed, relative to WT mice. The results from these studies demonstrate an in vivo mechanistic relationship between FVIIa, Egr-1 and the inflammatory response in keratinocyte function during the wound healing process.
Xu
Zhi
Z
WM Keck Center for Transgene Research and Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States of America.
Xu
Haifeng
H
Ploplis
Victoria A
VA
Castellino
Francis J
FJ
D000818:Animals; D002465:Cell Movement; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D005167:Factor VII / Q000235:genetics / Q000378:metabolism*; D005168:Factor VII Deficiency / Q000503:physiopathology*; D006651:Histocytochemistry; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D044464:Receptor, PAR-2 / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D013864:Thioglycolates; D013925:Thromboplastin / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology*
D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D044464:Receptor, PAR-2; D013864:Thioglycolates; D005167:Factor VII; D013925:Thromboplastin
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