title: Endoglin regulates cyclooxygenase-2 expression and activity.
abstract: 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 E(2) 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(omega)-nitro-l-arginine methyl ester induced a marked increase in COX-2 only in the normal Eng(+/+) mice. N(omega)-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-beta1 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.
authors.affiliation: Instituto Reina Sofía de Investigación Nefrológica, Departamento de Fisiología & Farmacología, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Jerkic
authors.forename: Juan V
authors.initials: JV
authors.lastname: Rivas-Elena
authors.forename: Juan F
authors.initials: JF
authors.lastname: Santibanez
authors.forename: Marta
authors.initials: M
authors.lastname: Prieto
authors.forename: Alicia
authors.initials: A
authors.lastname: Rodríguez-Barbero
authors.forename: Fernando
authors.initials: F
authors.lastname: Perez-Barriocanal
authors.forename: Miguel
authors.initials: M
authors.lastname: Pericacho
authors.forename: Miguel
authors.initials: M
authors.lastname: Arévalo
authors.forename: Calvin P H
authors.initials: CP
authors.lastname: Vary
authors.forename: Michelle
authors.initials: M
authors.lastname: Letarte
authors.forename: Carmelo
authors.initials: C
authors.lastname: Bernabeu
authors.forename: Jose M
authors.initials: JM
authors.lastname: López-Novoa
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D015232:Dinoprostone / Q000652:urine; D000071063:Endoglin; D004730:Endothelium, Vascular / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006579:Heterozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis; D011401:Promoter Regions, Genetic; D011956:Receptors, Cell Surface / Q000502:physiology; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000209:etiology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D011956:Receptors, Cell Surface; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D009569:Nitric Oxide; D051546:Cyclooxygenase 2; D015232:Dinoprostone