VEGF nuclear accumulation correlates with phenotypical changes in endothelial cells.
Vascular endothelial growth factor (VEGF) is a multifunctional cytokine that plays a prominent role in normal vascular biology and pathology. In an experimental wound model, the mechanical disruption of monolayers of cultured endothelial cells resulted in two phenotypically distinct cell subpopulations 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 endocytosis pathway and accumulated in the endosomal compartment, whereas in the cells situated at the edges of a wound, VEGF was rapidly taken up and translocated to the nucleus. VEGF internalization and subsequent nuclear accumulation only occurred for a short period of time after the wounding and was specifically abolished by antibodies that bind to the KDR binding site of VEGF. In the cells with VEGF nuclear accumulation, the levels of wound healing related proteins, such as Factor VIII (FVIII), tissue factor (TF) and tissue plasminogen activator, rapidly and dramatically increased compared to the cells that internalized VEGF via the classical endocytotic pathway. The increase in FVIII and TF was abolished when the nuclear transport is blocked. These data suggest that nuclear VEGF accumulation may be involved in modulating the levels of the proteins of the coagulation and fibrinolysis pathways.
Li
W
W
Department of Pharmacokinetics and Metabolism, Genentech, Inc., South San Francisco, CA 94080, USA.
Keller
G
G
D000302:Adrenal Cortex / Q000166:cytology / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D016228:Endothelial Growth Factors / Q000378:metabolism*; D004727:Endothelium / Q000166:cytology / Q000378:metabolism; D005169:Factor VIII / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D008222:Lymphokines / Q000378:metabolism*; D010641:Phenotype; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013925:Thromboplastin / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014945:Wound Healing
D016228:Endothelial Growth Factors; D008222:Lymphokines; D016760:Proto-Oncogene Proteins c-fos; D016271:Proto-Oncogene Proteins c-myc; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D005169:Factor VIII; D013925:Thromboplastin