title: Insulin Induces Relaxation and Decreases Hydrogen Peroxide-Induced Vasoconstriction in Human Placental Vascular Bed in a Mechanism Mediated by Calcium-Activated Potassium Channels and L-Arginine/Nitric Oxide Pathways.
abstract: HIGHLIGHTSShort-term incubation with insulin increases the L-arginine transport in HUVECs.Short-term incubation with insulin increases the NO synthesis in HUVECs.Insulin induces relaxation in human placental vascular bed.Insulin attenuates the constriction induced by hydrogen peroxide in human placenta.The relaxation induced by insulin is dependent on BKCa channels activity in human placenta. Insulin induces relaxation in umbilical veins, increasing the expression of human amino acid transporter 1 (hCAT-1) and nitric oxide synthesis (NO) in human umbilical vein endothelial cells (HUVECs). Short-term effects of insulin on vasculature have been reported in healthy subjects and cell cultures; however, its mechanisms remain unknown. The aim of this study was to characterize the effect of acute incubation with insulin on the regulation of vascular tone of placental vasculature. HUVECs and chorionic vein rings were isolated from normal pregnancies. The effect of insulin on NO synthesis, L-arginine transport, and hCAT-1 abundance was measured in HUVECs. Isometric tension induced by U46619 (thromboxane A2analog) or hydrogen peroxide (H2O2) were measured in vessels previously incubated 30 min with insulin and/or the following pharmacological inhibitors: tetraethylammonium (KCa channels), iberiotoxin (BKCa channels), genistein (tyrosine kinases), and wortmannin (phosphatidylinositol 3-kinase). Insulin increases L-arginine transport and NO synthesis in HUVECs. In the placenta, this hormone caused relaxation of the chorionic vein, and reduced perfusion pressure in placental cotyledons. In vessels pre-incubated with insulin, the constriction evoked by H2O2and U46619 was attenuated and the effect on H2O2-induced constriction was blocked with tetraethylammonium and iberiotoxin, but not with genistein, or wortmannin. Insulin rapidly dilates the placental vasculature through a mechanism involving activity of BKCa channels and L-arginine/NO pathway in endothelial cells. This phenomenon is related to quick increases of hCAT-1 abundance and higher capacity of endothelial cells to take up L-arginine and generate NO.
authors.affiliation: Vascular Physiology Laboratory, Department of Physiology, Faculty of Biological Sciences, Universidad de ConcepciónConcepción, Chile; Department of Morphophysiology, Faculty of Medicine, Universidad Diego PortalesSantiago, Chile.
authors.forename: Lissette
authors.initials: L
authors.lastname: Cabrera
authors.affiliation: Vascular Physiology Laboratory, Department of Physiology, Faculty of Biological Sciences, Universidad de Concepción Concepción, Chile.
authors.forename: Andrea
authors.initials: A
authors.lastname: Saavedra
authors.affiliation: Vascular Physiology Laboratory, Department of Physiology, Faculty of Biological Sciences, Universidad de Concepción Concepción, Chile.
authors.forename: Susana
authors.initials: S
authors.lastname: Rojas
authors.affiliation: Department of Obstetrics and Childcare, Faculty of Medicine, Universidad de Concepción Concepción, Chile.
authors.forename: Marcela
authors.initials: M
authors.lastname: Cid
authors.affiliation: Vascular Physiology Laboratory, Department of Physiology, Faculty of Biological Sciences, Universidad de Concepción Concepción, Chile.
authors.forename: Cristina
authors.initials: C
authors.lastname: Valenzuela
authors.affiliation: Vascular Physiology Laboratory, Department of Physiology, Faculty of Biological Sciences, Universidad de Concepción Concepción, Chile.
authors.forename: David
authors.initials: D
authors.lastname: Gallegos
authors.affiliation: Vascular Physiology Laboratory, Department of Physiology, Faculty of Biological Sciences, Universidad de Concepción Concepción, Chile.
authors.forename: Pamela
authors.initials: P
authors.lastname: Careaga
authors.affiliation: Vascular Physiology Laboratory, Department of Physiology, Faculty of Biological Sciences, Universidad de Concepción Concepción, Chile.
authors.forename: Emerita
authors.initials: E
authors.lastname: Basualto
authors.affiliation: Vascular Physiology Laboratory, Department of Physiology, Faculty of Biological Sciences, Universidad de Concepción Concepción, Chile.
authors.forename: Astrid
authors.initials: A
authors.lastname: Haensgen
authors.affiliation: Department of Pathophysiology, Faculty of Biological Sciences, Universidad de Concepción Concepción, Chile.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Peña
authors.affiliation: Department of Pathophysiology, Faculty of Biological Sciences, Universidad de Concepción Concepción, Chile.
authors.forename: Coralia
authors.initials: C
authors.lastname: Rivas
authors.affiliation: Department of Pathophysiology, Faculty of Biological Sciences, Universidad de Concepción Concepción, Chile.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Vera
authors.affiliation: Department of Pathophysiology, Faculty of Biological Sciences, Universidad de ConcepciónConcepción, Chile; Group of Research and Innovation in Vascular Health (GRIVAS Health)Chillán, Chile.
authors.forename: Victoria
authors.initials: V
authors.lastname: Gallardo
authors.affiliation: Centro de Investigaciones Médicas (CIM), School of Medicine, Universidad de Talca Talca, Chile.
authors.forename: Leandro
authors.initials: L
authors.lastname: Zúñiga
authors.affiliation: Group of Research and Innovation in Vascular Health (GRIVAS Health)Chillán, Chile; Vascular Physiology Laboratory, Group of Investigation in Tumor Angiogenesis (GIANT), Department of Basic Sciences, Universidad del BiobíoChillán, Chile.
authors.forename: Carlos
authors.initials: C
authors.lastname: Escudero
authors.affiliation: Cellular and Molecular Physiology Laboratory (CMPL), Division of Obstetrics and Gynecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de ChileSantiago, Chile; Department of Physiology, Faculty of Pharmacy, Universidad de SevillaSeville, Spain; University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine and Biomedical Sciences, University of QueenslandHerston, QLD, Australia.
authors.forename: Luis
authors.initials: L
authors.lastname: Sobrevia
authors.affiliation: Maternal and Fetal Health Research Centre, Institute of Human Development, University of ManchesterManchester, UK; Maternal and Fetal Health Research Centre, St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science CentreManchester, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Wareing
authors.affiliation: Vascular Physiology Laboratory, Department of Physiology, Faculty of Biological Sciences, Universidad de ConcepciónConcepción, Chile; Group of Research and Innovation in Vascular Health (GRIVAS Health)Chillán, Chile.
authors.forename: Marcelo
authors.initials: M
authors.lastname: González
keywords: BKCa channels; L-arginine; hCAT-1; insulin; nitric oxide; placenta