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Blood, 15 April 2004, Vol. 103, No. 8, pp. 3005-3012.
Prepublished online as a Blood First Edition Paper on December 11, 2003; DOI 10.1182/blood-2003-07-2459.
Submitted July 22, 2003
Accepted November 16, 2003
Gas1 is induced by VE-cadherin and vascular endothelial growth factor and inhibits endothelial cell apoptosis
Raffaella Spagnuolo, Monica Corada, Fabrizio Orsenigo, Lucia Zanetta, Ulrich Deuschle, Peter Sandy, Claudio Schneider, Christopher J Drake, Ferruccio Breviario, and Elisabetta Dejana*
FIRC Institute of Molecular Oncology, Milan, Italy; Department of Immunology and Cellular Biology, Mario Negri Institute for Pharmacological Research, Milan, Italy; Department of Biomolecular and Biotechnological Sciences, University of Milan, Milan, Italy
LION Bioscience AG, Heidelberg, Germany
Laboratorio Nazionale CIB, Area Science Park, Trieste, Italy
Department of Cell Biology, Medical University of South Carolina, Charleston, SC, USA
* Corresponding author; email: dejana{at}ifom-firc.it.
The junctional membrane protein VE-cadherin mediates contact inhibition of growth and inhibits apoptosis of endothelial cells. In this paper we show that VE-cadherin induces expression of Gas1, an integral membrane protein upregulated in non-proliferating cells. By comparing syngenic endothelial cell lines, we found that Gas1 mRNA was increased by three folds in VE-cadherin positive cells in comparison to VE-cadherin null cells. Ectopic expression of Gas1 in endothelial or 293 cells strongly reduced apoptosis without affecting cell growth. Addition of vascular endothelial growth factor (VEGF) also upregulated Gas1 and this effect was augmented in confluent non-proliferating cells than in sparse cultures. VE-cadherin blocking antibody partially inhibited VEGF induced Gas1, suggesting that VE-cadherin clustering is required for an optimal response to this stimulus. Inhibition of PI-3-kinase pathway by Wortmannin prevented Gas1 synthesis and the anti-apoptotic effect of VEGF, but, in cells ectopically expressing Gas1, Wortmannin was ineffective. Furthermore, inhibition of Gas1 expression by siRNA both in vitro and in allantois organ cultures, made endothelial cells refractory to the antiapoptotic effect of VEGF. Overall these data indicate that Gas1 induction by VE-cadherin and VEGF in endothelial cells requires activation of PI-3-kinase. Gas1 expression positively correlates with inhibition of endothelial cell apoptosis and may contribute to the integrity of resting endothelium.
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