Erythropoietin Triggers a Signaling Pathway in Endothelial Cells and Increases the Thrombogenicity of their Extracellular Matrices In Vitro

Berta Fusté; Mireia Serradell; Ginés Escolar; Aleix Cases; Roberto Mazzara; Ricardo Castillo; Antonio Ordinas; Maribel Díaz-Ricart

doi:10.1055/s-0037-1613275

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2002; 88(04): 678-685
DOI: 10.1055/s-0037-1613275

Review Article

Schattauer GmbH

Erythropoietin Triggers a Signaling Pathway in Endothelial Cells and Increases the Thrombogenicity of their Extracellular Matrices In Vitro

Autoren

Berta Fusté

¹Servicios de Hemoterapia-Hemo stasia y Nefrología, Hospital Clínic, IDIBAPS, Barcelona, Spain
Mireia Serradell

¹Servicios de Hemoterapia-Hemo stasia y Nefrología, Hospital Clínic, IDIBAPS, Barcelona, Spain
Ginés Escolar

¹Servicios de Hemoterapia-Hemo stasia y Nefrología, Hospital Clínic, IDIBAPS, Barcelona, Spain
Aleix Cases

¹Servicios de Hemoterapia-Hemo stasia y Nefrología, Hospital Clínic, IDIBAPS, Barcelona, Spain
Roberto Mazzara

¹Servicios de Hemoterapia-Hemo stasia y Nefrología, Hospital Clínic, IDIBAPS, Barcelona, Spain
Ricardo Castillo

¹Servicios de Hemoterapia-Hemo stasia y Nefrología, Hospital Clínic, IDIBAPS, Barcelona, Spain
Antonio Ordinas

¹Servicios de Hemoterapia-Hemo stasia y Nefrología, Hospital Clínic, IDIBAPS, Barcelona, Spain
Maribel Díaz-Ricart

¹Servicios de Hemoterapia-Hemo stasia y Nefrología, Hospital Clínic, IDIBAPS, Barcelona, Spain

Abstract

Summary

We demonstrate that exposure of cultured human endothelial cells to rHuEPO resulted in a dose-dependent increase in the tyrosine kinase activity, with phosphorylation of JAK-2 followed by rapid phosphorylation of STAT-5. Simultaneously, rHuEPO induced long-lasting phosphorylation of MAPK p42/44. Activation of this signaling pathways was directly associated with an increase in the thrombogenic properties of the extracellular matrix generated by these cells, when they were exposed to flowing blood. The enhancement in the reactivity of the resulting extracellular matrix towards platelets was associated with a higher expression of tissue factor. All these effects were blocked by an antibody to the EPO receptor and by specific inhibitors of tyrosine phosphorylation. The observed action of rHuEPO on endothelial cells seemed to be specifically triggered by the subsequent events that follow receptor binding, and occurred even at pharmacological concentrations of the cytokine. Our results indicate that rHuEPO has a direct action on the endothelium, increasing the reactivity of the underlying extracellular matrix towards platelets, effect that may be attributed to an increase in the expression of TF.

Keywords

Erythropoietin - endothelium - tyrosine phosphorylation - thrombosis - tissue factor

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