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(Circulation Research. 2006;99:248.)
© 2006 American Heart Association, Inc.

Molecular Medicine

Endoglin Regulates Cyclooxygenase-2 Expression and Activity

Mirjana Jerkic, Juan V. Rivas-Elena, Juan F. Santibanez, Marta Prieto, Alicia Rodríguez-Barbero, Fernando Perez-Barriocanal, Miguel Pericacho, Miguel Arévalo, Calvin P.H. Vary, Michelle Letarte, Carmelo Bernabeu, Jose M. López-Novoa

From the Instituto "Reina Sofía" de Investigación Nefrológica (M.J., J.V.R.-E., M.Prieto, A.R.-B., F.P.-B., M.Pericacho, J.M.L.-N.), Departamento de Fisiología & Farmacología, Universidad de Salamanca, Salamanca, Spain; Hospital for Sick Children (M.J., M.L.), and Heart and Stroke Lewar Center of Excellence, University of Toronto, Toronto, Canada, Centro de Investigaciones Biológicas (J.F.S., C.B.), Consejo Superior de Investigaciones Científicas, Madrid, Spain, Laboratorio de Biologia Celular (J.F.S.), Instituto de Nutricion y Tecnologia de los Alimentos, INTA, Universidad de Chile, Santiago, Chile, Departamento de Anatomía e Histología Humanas (M.A.), Universidad de Salamanca, Salamanca, Spain, Center for Molecular Medicine (C.P.H.V.), Maine Medical Center Research Institute, Scarborough, Me.

Correspondence to J.M. López-Novoa, Departamento de Fisiología y Farmacología, Edificio Departamental. Campus Miguel de Unamuno, 37007 Salamanca Spain. E-mail jmlnovoa{at}usal.es

The endoglin heterozygous (Eng^+/–) mouse, which serves as a model of hereditary hemorrhagic telangiectasia (HHT), was shown to express reduced levels of endothelial NO synthase (eNOS) with impaired activity. Because of intricate changes in vasomotor function in the Eng^+/– mice and the potential interactions between the NO- and prostaglandin-producing pathways, we assessed the expression and function of cyclooxygenase (COX) isoforms. A specific upregulation of COX-2 in the vascular endothelium and increased urinary excretion of prostaglandin E₂ were observed in the Eng^+/– mice. Specific COX-2 inhibition with parecoxib transiently increased arterial pressure in Eng^+/– but not in Eng^+/+ mice. Transfection of endoglin in L6E9 myoblasts, shown previously to stimulate eNOS expression, led to downregulation of COX-2 with no change in COX-1. In addition, COX-2 promoter activity and protein levels were inversely correlated with endoglin levels, in doxycyclin-inducible endothelial cells. Chronic NO synthesis inhibition with N-nitro-L-arginine methyl ester induced a marked increase in COX-2 only in the normal Eng^+/+ mice. N-nitro-L-arginine methyl ester also increased COX-2 expression and promoter activity in doxycyclin-inducible endoglin expressing endothelial cells, but not in control cells. The level of COX-2 expression following transforming growth factor-ß1 treatment was less in endoglin than in mock transfected L6E9 myoblasts and was higher in human endothelial cells silenced for endoglin expression. Our results indicate that endoglin is involved in the regulation of COX-2 activity. Furthermore, reduced endoglin levels and associated impaired NO production may be responsible, at least in part, for augmented COX-2 expression and activity in the Eng^+/– mice.

Key Words: endoglin • COX-2 • NO • TGF-ß1

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