Granulocyte/macrophage colony-stimulating factor treatment of human chronic ulcers promotes angiogenesis associated withde novovascular endothelial growth factor transcription in the ulcer bed

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Abstract
Background Granulocyte/macrophage colony‐stimulating factor (GM‐CSF), a cytokine with pleiotropic functions, has been successfully employed in the treatment of chronic skin ulcers. The biological effects underlying GM‐CSF action in impaired wound healing have been only partly clarified. Objectives To investigate the effects of GM‐CSF treatment of chronic venous ulcers on lesion vascularization and on the local synthesis of the angiogenic factors vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF). Methods Patients with nonhealing venous leg ulcers were treated with intradermal injection of recombinant human GM‐CSF, and biopsies were taken at the ulcer margin before and 5 days after administration. Wound vascularization was analysed by immunohistochemistry using antiplatelet endothelial cell adhesion molecule‐1/CD31 and anti‐α‐smooth muscle actin antibodies. VEGF and PlGF transcription was assessed by in situ hybridization. To identify the cell populations transcribing VEGF within the ulcer bed, the VEGF hybridization signal was correlated with the immunostaining for different cell type markers on serial sections. Direct induction of VEGF transcription by GM‐CSF was investigated in GM‐CSF‐treated cultured macrophages and keratinocytes. Results Blood vessel density was significantly increased in the ulcer bed following GM‐CSF treatment. VEGF transcripts were localized in keratinocytes at the ulcer margin both before and after GM‐CSF treatment, whereas a VEGF hybridization signal was evident within the ulcer bed only following administration. PlGF mRNA was barely detectable in keratinocytes at the ulcer margin and was not visibly increased after treatment. Unlike VEGF, a specific PlGF hybridization signal could not be detected in cells within the ulcer following GM‐CSF administration. Monocytes/macrophages were the main cell population transcribing VEGF after GM‐CSF treatment. In vitro analysis demonstrated that VEGF transcription can be directly stimulated by GM‐CSF in a differentiated monocytic cell line, but not in keratinocytes. Conclusions Our data show that increased vascularization is associated with GM‐CSF treatment of chronic venous ulcers and indicate that inflammatory cell‐derived VEGF may act as an angiogenic mediator of the healing effect of GM‐CSF in chronic ulcers.

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