An autocrine loop mediates expression of vascular endothelial growth factor in human dermal microvascular endothelial cells

The expression of vascular endothelial growth factor mRNA and protein is re gulated by a number of agents including growth factors, cytokines, and phor bol esters, Here we report that vascular endothelial growth factor is able to increase its own level in cultured human dermal microvascular endothelia l cells. Accumulation of vascular endothelial growth factor mRNA and polype ptide can be detected as early as 4 h after addition of vascular endothelia l growth factor to the cell culture medium. The autocrine action of vascula r endothelial growth factor appears to be mediated by the KDR receptor. The increase of its own message by vascular endothelial growth factor is block ed by the transcription inhibitor actinomycin D, Transient transfection exp eriments performed with human dermal microvascular endothelial cells and us ing a 3.2 kb human vascular endothelial growth factor promoter fragment sho wed that vascular endothelial growth factor auto-induction can be mimicked at the promoter level. This indicates that the observed vascular endothelia l growth factor mRNA increase after vascular endothelial growth factor trea tment is occurring at the level of transcription. Furthermore, vascular end othelial growth factor auto-induction is inhibited by PD 098059, showing th at phosphorylation events, catalyzed by mitogen activated protein kinases, are a prerequisite for the vascular endothelial growth factor effect. Exami nation of extracellular signal-regulated kinase and c-Jun N-terminal protei n kinase catalytic activities showed that both enzymes have to be activated to mediate the vascular endothelial growth factor signal. Our data demonst rate for the first time the existence of an autocrine loop for vascular end othelial growth factor in endothelial cells. Most probably this represents an amplification mechanism for the action of vascular endothelial growth fa ctor in the microvascularization process.