VEGF nuclear accumulation correlates with phenotypical changes in endothelial cells

Vascular endothelial growth factor (VEGF) is a multifunctional cytokine tha t plays a prominent role in normal vascular biology and pathology. In an ex perimental wound model, the mechanical disruption of monolayers of cultured endothelial cells resulted in two phenotypically distinct cell subpopulati ons in which VEGF was internalized by alternative endocytotic pathways and delivered to different subcellular compartments. In the cells away from the wound, VEGF was internalized via the classical receptor-mediated endocytos is pathway and accumulated in the endosomal compartment, whereas in the cel ls situated at the edges of a wound, VEGF was rapidly taken up and transloc ated to the nucleus, VEGF internalization and subsequent nuclear accumulati on only occurred for a short period of time after the wounding and was spec ifically abolished by antibodies that bind to the KDR binding site of VEGF. In the cells with VEGF nuclear accumulation, the levels of wound healing re lated proteins, such as Factor VIII (FVIII), tissue factor (TF) and tissue plasminogen activator, rapidly and dramatically increased compared to the c ells that internalized VEGF via the classical endocytotic pathway. The incr ease in FVIII and TF was abolished when the nuclear transport is blocked. T hese data suggest that nuclear VEGF accumulation may be involved in modulat ing the levels of the proteins of the coagulation and fibrinolysis pathways .