Hepatocyte Growth Factor/Scatter Factor (HGF/SF) Induces Vascular Permeability Factor (VPF/VEGF) Expression by Cultured Keratinocytes

• Published in: Journal of investigative dermatology Vol. 111; no. 6; pp. 1160 - 1165
• Main Authors: Gille, Jens, Khalik, Mona, König, Veronika, Kaufmann, Roland
• Format: Journal Article
• Language: English
• Published: Danvers, MA Elsevier Inc 01.12.1998; Nature Publishing
• Subjects: 5' Untranslated Regions; angiogenesis; Biological and medical sciences; Cell Line; Cycloheximide - pharmacology; Dermatology; Endothelial Growth Factors - chemistry; Endothelial Growth Factors - genetics; Fibroblasts - metabolism; Gene Expression - drug effects; gene expression regulation; Genistein - pharmacology; Growth Inhibitors - pharmacology; Hepatocyte Growth Factor - pharmacology; Humans; Investigative techniques, diagnostic techniques (general aspects); Keratinocytes - cytology; Keratinocytes - metabolism; Lymphokines - chemistry; Lymphokines - genetics; Medical sciences; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Phosphorylation - drug effects; Protein Synthesis Inhibitors - pharmacology; RNA, Messenger - metabolism; Tyrosine; Up-Regulation; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; gene expression regulation; angiogenesis; Human; Angiogenesis; Cell culture; Vascular endothelium growth factor; Hepatocyte growth factor; Epidermis; Keratinocyte; Skin
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1046/j.1523-1747.1998.00418.x

Skin expression of the endothelial cell-specific vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) as an outstanding mediator of physiologic and pathologic angiogenesis has been previously demonstrated to be subject to regulation by distinct stimuli. We explored whether the multifunctional hepatocyte growth factor/scatter factor (HGF/SF) may mediate its angiogenic properties in part through paracrine induction of cutaneous VPF/VEGF synthesis. In these studies, we demonstrate that HGF/SF functions as a potent inducer of VPF/VEGF expression by human epidermal keratinocytes and by different epithelial-derived cellsin vitro. VPF/VEGF mRNA and protein expression are regulated by HGF/SF in both a concentration- and a time-dependent fashion. Examination of mRNA half-lives does not reveal an increase in VPF/VEGF mRNA stability after HGF/SF stimulation. Thus, HGF/SF-induced VPF/VEGF mRNA expression appears to be largely dependent on enhanced gene transcription. In analyses of transiently transfected 5′-deletional reporter gene constructs, we identified a GC-rich VPF/VEGF promoter element that conveys transcriptional activation in response to HGF/SF. This sequence, located between nucleotides –88 and –70, is critical for both constitutive and HGF/SF-induced transcriptional activity. Together, our observations support a model in which HGF/SF mediates angiogenic properties in part through paracrine induction of VPF/VEGF synthesis by keratinocytes. In addition to cutaneous inflammation and wound healing, our findings have potential significance for vascular hyperpermeability and angiogenesis in tumor growth.