VEGF-mediated endothelial P-selectin translocation: role of VEGF receptors and endogenous PAF synthesis.
The acute increase in vascular permeability produced by vascular endothelial growth factor (VEGF-A(165)) requires activation of endothelial Flk-1 receptors (VEGFR-2) and stimulation of platelet-activating factor (PAF) synthesis. Like PAF, VEGF-A(165) promotes translocation of P-selectin to the endothelial cell (EC) surface. However, the mechanisms involved remain unknown. By treating human umbilical vein endothelial cells (HUVECs) with VEGF analogs, we show that activation of VEGFR-1 or VEGFR-2 or both induced a rapid and transient translocation of endothelial P-selectin and neutrophil adhesion to activated ECs. The effects mediated by VEGF-A(165) and VEGF-A(121) (VEGFR-1/VEGFR-2 agonists) were blocked by a selective VEGFR-2 inhibitor, SU1498. VEGF-A(165) was twice as potent as VEGF-A(121), which can be explained by the binding capacity of VEGF-A(165) to its coreceptor neuropilin-1 (NRP-1). Indeed, treatment with NRP-1 antagonist (GST-Ex7) reduced the effect of VEGF-A(165) to the levels observed upon stimulation with VEGF-A(121). Finally, the use of selective PAF receptor antagonists reduced VEGF-A(165)-mediated P-selectin translocation. Together, these data show that maximal P-selectin translocation and subsequent neutrophil adhesion was mediated by VEGF-A(165) on the activation of VEGFR-2/NRP-1 complex and required PAF synthesis.
Rollin
Simon
S
Department of Pharmacology, University of Montreal, Montreal, QC, Canada.
Lemieux
Caroline
C
Maliba
Ricardo
R
Favier
Judith
J
Villeneuve
Louis R
LR
Allen
Bruce G
BG
Soker
Shay
S
Bazan
Nicolas G
NG
Merhi
Yahye
Y
Sirois
Martin G
MG
D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology*; D006801:Humans; D039942:Neuropilin-1 / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology; D019007:P-Selectin / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000096:biosynthesis / Q000502:physiology*; D021381:Protein Transport; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism* / Q000502:physiology; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000031:analogs & derivatives / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D019007:P-Selectin; D010972:Platelet Activating Factor; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; D040262:Receptors, Vascular Endothelial Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2