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J. Biol. Chem., Vol. 279, Issue 40, 41611-41618, October 1, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/40/41611    most recent M407981200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mason, J. C. Articles by Haskard, D. O. Search for Related Content PubMed PubMed Citation Articles by Mason, J. C. Articles by Haskard, D. O. Social Bookmarking                      What's this?

Decay-accelerating Factor Induction on Vascular Endothelium by Vascular Endothelial Growth Factor (VEGF) Is Mediated via a VEGF Receptor-2 (VEGF-R2)- and Protein Kinase C-/ (PKC/)-dependent Cytoprotective Signaling Pathway and Is Inhibited by Cyclosporin A^*

Justin C. Mason, Rivka Steinberg, Elaine A. Lidington, Anne R. Kinderlerer, Motoi Ohba¶, and Dorian O. Haskard

From the British Heart Foundation Cardiovascular Medicine Unit, Eric Bywaters Center, Imperial College London, Hammersmith Hospital, London W12 0NN, United Kingdom and the ^¶Institute of Molecular Oncology, Showa University, Shinagawa, Tokyo 142-8555, Japan

Decay-accelerating factor (DAF), a membrane-bound complement regulatory protein, is up-regulated on endothelial cells (ECs) following treatment with vascular endothelial growth factor (VEGF), providing enhanced protection from complement-mediated injury. We explored the signaling pathways involved in this response. Incubation of human umbilical vein ECs with VEGF induced a 3-fold increase in DAF expression. Inhibition by flk-1 kinase inhibitor SU1498 and failure of placental growth factor (PlGF) to up-regulate DAF confirmed the role of VEGF-R2. The response was also blocked by pretreatment with phospholipase C- (PLC) inhibitor U71322 and protein kinase C (PKC) antagonist GF109203X. In contrast, no effect was seen with nitric oxide synthase inhibitor N^G-monomethyl-L-arginine (L-NMMA). Use of PKC agonists and isozyme-specific pseudosubstrate peptide antagonists suggested a role for PKC and - in VEGF-mediated DAF up-regulation. This was confirmed by transfection of ECs with PKC and - dominant-negative constructs, which in combination completely abrogated induction of DAF by VEGF. In contrast, LY290042, a phosphoinositide 3-kinase (PI3K) inhibitor, significantly augmented DAF expression, suggesting a negative regulatory role for phosphoinositide 3-kinase. 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-, phospholipase C--, and PKC/-mediated cytoprotective pathway in ECs. 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.

Received for publication, July 15, 2004 , and in revised form, July 27, 2004.

^* This work was supported by Arthritis Research Campaign Senior Fellowship M0664 (to J. C. M.). 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.

To whom correspondence should be addressed: Cardiovascular Medicine Unit, Eric Bywaters Center, Imperial College London, Hammersmith Hospital, Du Cane Rd., London W12 0NN, United Kingdom. Tel.: 44-20-8383-1622; Fax: 44-20-8383-1640; E-mail: justin.mason{at}imperial.ac.uk.

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