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Papers In Press, published online ahead of print July 28, 2004
Cardiovascular Medicine Unit, Imperial College London, Hammersmith Hospital, London W12 ONN
Corresponding Author: justin.mason{at}imperial.ac.uk
Decay-accelerating factor (DAF), a membrane-bound complement regulatory protein, is upregulated on endothelial cells (EC) following treatment with VEGF, providing enhanced protection from complement-mediated injury. We explored the signaling pathways involved in this response. Incubation of human umbilical vein EC with VEGF induced a 3-fold increase in DAF expression. Inhibition by flk-1 kinase inhibitor SU1498, and failure of PlGF to upregulate DAF, confirmed the role of VEGF-R2. The response was also blocked by pre-treatment with PLC
J. Biol. Chem, 10.1074/jbc.M407981200
Submitted on July 15, 2004
Revised on July 27, 2004
Accepted on July 28, 2004
Decay-accelerating factor induction on vascular endothelium by VEGF is mediated via a VEGF-R2 and PKC
/
-dependent cytoprotective signaling pathway and is inhibited by cyclosporin A
inhibitor U71322 and PKC antagonist GF109203X. In contrast, no effect was seen with nitric oxide synthase inhibitor L-NMMA. Use of PKC agonists and isozyme-specific pseudosubstrate peptide antagonists suggested a role for PKC
and 
in VEGF-mediated DAF upregulation. This was confirmed by transfection of EC with PKC and dominant-negative constructs, which, in combination, completely abrogated induction of DAF by VEGF. In contrast, LY290042, a PI-3K inhibitor, significantly augmented DAF expression suggesting a negative regulatory role for PI-3K. The widely used immunosuppressive drug cyclosporin A (CsA) inhibited DAF induction by VEGF in a dose-dependent manner. The VEGF-induced DAF expression was functionally effective, significantly reducing complement-mediated EC lysis and this cytoprotective effect was reversed by CsA. These data provide evidence for a VEGF-R2, PLC, PKC/-mediated cytoprotective pathway in EC. This may represent an important mechanism for the maintenance of vascular integrity during chronic inflammation involving complement activation. Moreover, inhibition of this pathway by CsA may play a role in CsA-mediated vascular injury.
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