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(Circulation Research. 2002;91:202.)
© 2002 American Heart Association, Inc.

Molecular Medicine

Cyclophilin-Mediated Pathways in the Effect of Cyclosporin A on Endothelial Cells

Role of Vascular Endothelial Growth Factor

M. Victoria Alvarez-Arroyo, Susana Yagüe, Ronald M. Wenger, Daniel S. Pereira, Sonsoles Jiménez, Francisco R. González-Pacheco, M. Angeles Castilla, Juan José P. Deudero, Carlos Caramelo

From the Laboratorio de Nefrología-Hipertensión (M.V.A.-A., S.Y., S.J., F.R.G.-P., M.A.C., J.J.P.D., C.C.), Fundación Jiménez Díaz, Universidad Autónoma, Instituto Reina Sofía de Investigación Nefrológica, Madrid, Spain; Wenger CHEMTECH (R.M.W.), Riehen, Switzerland; and the Molecular and Cell Biology Department (D.S.P.), ImClone Systems Inc, New York, NY.

Correspondence to C. Caramelo, MD, Lab. de Nefrología e Hipertensión, Fundación Jiménez Díaz, Universidad Autónoma, Av Reyes Católicos 2, 28040, Madrid, Spain. E-mail ccaramelo{at}fjd.es

The relative importance of cyclophilin (CyP) versus calcineurin (Cn)-mediated mechanisms in the effect of cyclosporin A (CsA) on endothelial cells (ECs) is largely unknown. In cultured ECs, CsA was cytotoxic/proapoptotic or cytoprotective/antiapoptotic at high or low concentrations, respectively. CsA analogs (MeVal-4-CsA and MeIle-4-CsA), which bind to CyP but do not inhibit Cn, closely reproduced the CsA effects. Based on our previous data, the role of vascular endothelial growth factor (VEGF) as a mediator of CsA-induced cytoprotection was further analyzed. The actions of CsA and CsA analogs were shifted from a protective to a cell-damaging pattern in the presence of a specific anti-VEGF monoclonal antibody (mAb). This positive interaction was further supported by a transient increase in cytosolic free calcium concentration ([Ca²⁺]_i) by VEGF after pretreatment with either CsA or MeVal-4-CsA and an increase in the expression and synthesis of VEGF receptor 2 (VEGFR2). Of functional importance, blockade of the interaction between VEGF and VEGFR2 by a VEGFR2 mAb abolished the cytoprotective effect of CsA. In addition, preconditioning with low concentrations of CsA or CsA analogs increased both cytoprotection and VEGFR2 mRNA expression when EC were exposed to higher concentrations of CsA. In summary, our results reveal that (1) the biphasic responses to CsA in EC are related to the interaction of CsA with CyP rather than with Cn and (2) VEGF is a critical factor in the cytoprotective effect of CsA, by a mechanism that involves VEGFR2.

Key Words: cyclosporin A • cylophilin-binding analogs • vascular endothelial growth factor • vascular endothelial growth factor receptor 2 • cytoprotection

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