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Blood, 15 May 2004, Vol. 103, No. 10, pp. 3789-3797.
Prepublished online as a Blood First Edition Paper on February 5, 2004; DOI 10.1182/blood-2003-07-2272.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
VEGF-mediated endothelial P-selectin translocation: role of VEGF receptors and endogenous PAF synthesis
Simon Rollin,
Caroline Lemieux,
Ricardo Maliba,
Judith Favier,
Louis R. Villeneuve,
Bruce G. Allen,
Shay Soker,
Nicolas G. Bazan,
Yahye Merhi, and
Martin G. Sirois
From the Montreal Heart Institute, Department of Pharmacology, University of Montreal, Montreal, QC, Canada; Department of Urology, Children's Hospital and Harvard Medical School, Boston, MA; and Neuroscience Center, Louisiana State University (LSU) Health Sciences Center, New Orleans.
The acute increase in vascular permeability produced by vascular endothelial growth factor (VEGF-A165) requires activation of endothelial Flk-1 receptors (VEGFR-2) and stimulation of platelet-activating factor (PAF) synthesis. Like PAF, VEGF-A165 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-A165 and VEGF-A121 (VEGFR-1/VEGFR-2 agonists) were blocked by a selective VEGFR-2 inhibitor, SU1498. VEGF-A165 was twice as potent as VEGF-A121, which can be explained by the binding capacity of VEGF-A165 to its coreceptor neuropilin-1 (NRP-1). Indeed, treatment with NRP-1 antagonist (GST-Ex7) reduced the effect of VEGF-A165 to the levels observed upon stimulation with VEGF-A121. Finally, the use of selective PAF receptor antagonists reduced VEGF-A165–mediated P-selectin translocation. Together, these data show that maximal P-selectin translocation and subsequent neutrophil adhesion was mediated by VEGF-A165 on the activation of VEGFR-2/NRP-1 complex and required PAF synthesis.
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