Hepatocyte growth factor scatter factor (HGF/SF) induces vascular permeability factor (VPF/VEGF) expression by cultured keratinocytes

Skin expression of the endothelial cell-specific vascular permeability fact or/vascular endothelial growth factor (VPF/VEGF) as an outstanding mediator of physiologic and pathologic angiogenesis has been previously demonstrate d to be subject to regulation by distinct stimuli. We explored whether the multifunctional hepatocyte growth factor/scatter factor (HGF/SF) may mediat e its angiogenic properties in part through paracrine induction of cutaneou s VPF/VEGF synthesis. In these studies, we demonstrate that HGF/SF function s as a potent inducer of VPF/VEGF expression by human epidermal keratinocyt es and by different epithelial-derived cells in vitro. VPF/VEGF mRNA and pr otein expression are regulated by HGF/SF in both a concentration- and a tim e-dependent fashion. Examination of mRNA half-lives does not reveal an incr ease in VPF/VEGF mRNA stability after HGF/SF stimulation. Thus, HGF/SF-indu ced VPF/VEGF mRNA expression appears to be largely dependent on enhanced ge ne transcription. In analyses of transiently transfected 5'-deletional repo rter gene constructs, we identified a GC-rich VPF/VEGF promoter element tha t conveys transcriptional activation in response Co HGF/SF, This sequence, located between nucleotides -88 and -70, is critical for both constitutive and HGF/SF-induced transcriptional activity. Together, our observations sup port 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 sign ificance for vascular hyperpermeability and angiogenesis in tumor growth.