Mechanisms of Signal Transduction
Vascular Endothelial Growth Factor (VEGF)-A165-induced Prostacyclin Synthesis Requires the Activation of VEGF Receptor-1 and -2 Heterodimer*

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We previously reported that vascular endothelial growth factor (VEGF)-A165 inflammatory effect is mediated by acute platelet-activating factor synthesis from endothelial cells upon the activation of VEGF receptor-2 (VEGFR-2) and its coreceptor, neuropilin-1 (NRP-1). In addition, VEGF-A165 promotes the release of other endothelial mediators including nitric oxide and prostacyclin (PGI2). However, it is unknown whether VEGF-A165 is mediating PGI2 synthesis through VEGF receptor-1 (VEGFR-1) and/or VEGF receptor-2 (VEGFR-2) activation and whether the coreceptor NRP-1 potentiates VEGF-A165 activity. In this study, PGI2 synthesis in bovine aortic endothelial cells (BAEC) was assessed by quantifying its stable metabolite (6-keto prostaglandin F, 6-keto PGF) by enzyme-linked immunosorbent assay. Treatment of BAEC with VEGF analogs, VEGF-A165 (VEGFR-1, VEGFR-2 and NRP-1 agonist) and VEGF-A121 (VEGFR-1 and VEGFR-2 agonist) (up to 10–9m), increased PGI2 synthesis by 70- and 40-fold within 15 min. Treatment with VEGFR-1 (placental growth factor and VEGF-B) or VEGFR-2 (VEGF-C) agonist did not increase PGI2 synthesis. The combination of VEGFR-1 and VEGFR-2 agonists did not increase PGI2 release. Pretreatment with a VEGFR-2 inhibitor abrogated PGI2 release mediated by VEGF-A165 and VEGF-A121, and pretreatment of BAEC with antisense oligomers targeting VEGFR-1 or VEGFR-2 mRNA reduced PGI2 synthesis mediated by VEGF-A165 and VEGF-A121 up to 79%. In summary, our data demonstrate that the activation of VEGFR-1 and VEGFR-2 heterodimer (VEGFR-1/R-2) is essential for PGI2 synthesis mediated by VEGF-A165 and VEGF-A121, which cannot be reproduced by the parallel activation of VEGFR-1 and VEGFR-2 homodimers with corresponding agonists. In addition, the binding of VEGF-A165 to NRP-1 potentiates its capacity to promote PGI2 synthesis.

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Recipient of a scholarship from the CIHR

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This work was supported by grants from Canadian Institutes of Health Research (CIHR) (MOP-43919), Heart and Stroke Foundation of Quebec, and Birks Family Foundation (to M. G. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.