title: Endothelial eNOS/arginase imbalance contributes to vascular dysfunction in IUGR umbilical and placental vessels.
abstract: Placental vascular tone is critically influenced by nitric oxide (NO) derived from endothelial NO synthase (eNOS) activity. Placental vessels from pregnancies complicated with intrauterine growth restriction present altered NOS-dependent vasodilation. Arginase-2 competes with eNOS for l-arginine and counteracts the NOS-dependent relaxation in umbilical vessels from normal pregnancies. However there is no data regarding the contribution of arginase activity on the impaired endothelial function in IUGR placenta. We studied whether arginase-2 participates in IUGR-related placental vascular dysfunction counteracting eNOS-dependent relaxation, and the regulation of arginase-2 and eNOS expression in endothelial cells from IUGR umbilical arteries (HUAEC) and veins (HUVEC). In IUGR-derived umbilical arteries (UA) and veins (UV), and chorionic arteries (CA), NOS-dependent vasoactive response in the presence and absence of BEC (arginase inhibitor) was studied. Protein levels of eNOS (total and Ser(1177)-P-eNOS), arginase-2 and arginase activity were determined in IUGR HUAEC and HUVEC. In IUGR vessels eNOS-dependent relaxation was reduced, being improved by BEC. This effect was higher in arteries than veins, and in chorionic compared with umbilical vessels. In cultured IUGR endothelial cells, arginase-2 protein expression and activity were increased in HUVEC, without changes in HUAEC. In IUGR-derived endothelium there was a generalized reduction in the in vitro eNOS activation (Ser(1177)-P-eNOS/eNOS), and therefore a decreased eNOS/arginase activity ratio. Here we provide ex vivo and in vitro evidence for a vascular role of arginase throughout placental vasculature, negatively controlling NOS activity. This effect seems to be crucial in the pathophysiology of endothelial dysfunction present in IUGR feto-placental vessels.
authors.affiliation: Division of Obstetrics and Gynecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Marcoleta 391, Santiago, Chile.
authors.forename: B J
authors.initials: BJ
authors.lastname: Krause
authors.forename: I
authors.initials: I
authors.lastname: Carrasco-Wong
authors.forename: A
authors.initials: A
authors.lastname: Caniuguir
authors.forename: J
authors.initials: J
authors.lastname: Carvajal
authors.forename: M
authors.initials: M
authors.lastname: Farías
authors.forename: P
authors.initials: P
authors.lastname: Casanello
mesh_terms: D000328:Adult; D001119:Arginase / Q000378:metabolism* / Q000502:physiology; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D005260:Female; D005317:Fetal Growth Retardation / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism* / Q000502:physiology; D010920:Placenta / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D021041:Placental Circulation / Q000502:physiology; D011247:Pregnancy; D014469:Umbilical Arteries / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*
chemical_list: C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C477631:ARG2 protein, human; D001119:Arginase