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 cells in 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.