Induction of vascular endothelial growth factor by platelet-activating factor and platelet-derived growth factor is downregulated by corticosteroids.
Vascular endothelial growth factor (VEGF) is a potent peptide growth factor specific for vascular endothelial cells, which promotes neovascularization and increases vascular permeability in vivo. Enhanced microvascular permeability and edema are common characteristics of inflammatory and neoplastic disorders. Two proinflammatory mediators, platelet-activating factor (PAF) and platelet-derived growth factor (PDGF), are known to contribute to cellular damage and tissue remodeling in a number of lung diseases. To determine whether PAF or PDGF induce VEGF gene expression in primary cultures of human pulmonary fibroblasts and pulmonary vascular smooth-muscle cells (VSMCs), we performed Northern-blot analysis and enzyme-linked immunosorbent assays (EIA). PAF and all three isoforms of PDGF (PDGF-AA, -AB, and -BB) increased VEGF mRNA in a time- and dose-dependent manner. While PAF was shown to increase VEGF mRNA at picomolar concentrations, all PDGF isoforms were effective in inducing VEGF mRNA at nanomolar concentrations. The transcriptional activation was accompanied by increased levels of VEGF protein as determined by EIA in culture medium. These results indicate that VEGF gene expression in VSMCs and fibroblasts is mediated by PAF and/or PDGF isoforms. In a paracrine mode of action, secreted VEGF may then lead to altered endothelial cell functions and vascular hyperpermeability. In the presence of the corticosteroids cortisone, hydrocortisone, dexamethasone, or prednisolone at nanomolar concentrations, this stimulus-dependent transcription of VEGF was abolished. The inhibitory effect of corticosteroids on VEGF expression could explain the clinically well-known antiedematous potency of corticosteroids on a molecular level.
Nauck
M
M
Department of Medicine, University Hospital Freiburg, Germany.
Roth
M
M
Tamm
M
M
Eickelberg
O
O
Wieland
H
H
Stulz
P
P
Perruchoud
A P
AP
D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects*; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008222:Lymphokines / Q000096:biosynthesis* / Q000235:genetics; D010972:Platelet Activating Factor / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000305:Adrenal Cortex Hormones; D016228:Endothelial Growth Factors; D008222:Lymphokines; D010972:Platelet Activating Factor; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors