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      The placental pursuit for an adequate oxidant balance between the mother and the fetus

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          Abstract

          The placenta is the exchange organ that regulates metabolic processes between the mother and her developing fetus. The adequate function of this organ is clearly vital for a physiologic gestational process and a healthy baby as final outcome. The umbilico-placental vasculature has the capacity to respond to variations in the materno-fetal milieu. Depending on the intensity and the extensity of the insult, these responses may be immediate-, mediate-, and long-lasting, deriving in potential morphostructural and functional changes later in life. These adjustments usually compensate the initial insults, but occasionally may switch to long-lasting remodeling and dysfunctional processes, arising maladaptation. One of the most challenging conditions in modern perinatology is hypoxia and oxidative stress during development, both disorders occurring in high-altitude and in low-altitude placental insufficiency. Hypoxia and oxidative stress may induce endothelial dysfunction and thus, reduction in the perfusion of the placenta and restriction in the fetal growth and development. This Review will focus on placental responses to hypoxic conditions, usually related with high-altitude and placental insufficiency, deriving in oxidative stress and vascular disorders, altering fetal and maternal health. Although day-to-day clinical practice, basic and clinical research are clearly providing evidence of the severe impact of oxygen deficiency and oxidative stress establishment during pregnancy, further research on umbilical and placental vascular function under these conditions is badly needed to clarify the myriad of questions still unsettled.

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          Most cited references137

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          A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation.

          We have identified a 50-nucleotide enhancer from the human erythropoietin gene 3'-flanking sequence which can mediate a sevenfold transcriptional induction in response to hypoxia when cloned 3' to a simian virus 40 promoter-chloramphenicol acetyltransferase reporter gene and transiently expressed in Hep3B cells. Nucleotides (nt) 1 to 33 of this sequence mediate sevenfold induction of reporter gene expression when present in two tandem copies compared with threefold induction when present in a single copy, suggesting that nt 34 to 50 bind a factor which amplifies the induction signal. DNase I footprinting demonstrated binding of a constitutive nuclear factor to nt 26 to 48. Mutagenesis studies revealed that nt 4 to 12 and 19 to 23 are essential for induction, as substitutions at either site eliminated hypoxia-induced expression. Electrophoretic mobility shift assays identified a nuclear factor which bound to a probe spanning nt 1 to 18 but not to a probe containing a mutation which eliminated enhancer function. Factor binding was induced by hypoxia, and its induction was sensitive to cycloheximide treatment. We have thus defined a functionally tripartite, 50-nt hypoxia-inducible enhancer which binds several nuclear factors, one of which is induced by hypoxia via de novo protein synthesis.
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            Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing.

            Multicellular organisms initiate adaptive responses when oxygen (O(2)) availability decreases, but the underlying mechanism of O(2) sensing remains elusive. We find that functionality of complex III of the mitochondrial electron transport chain (ETC) is required for the hypoxic stabilization of HIF-1 alpha and HIF-2 alpha and that an increase in reactive oxygen species (ROS) links this complex to HIF-alpha stabilization. Using RNAi to suppress expression of the Rieske iron-sulfur protein of complex III, hypoxia-induced HIF-1 alpha stabilization is attenuated, and ROS production, measured using a novel ROS-sensitive FRET probe, is decreased. These results demonstrate that mitochondria function as O(2) sensors and signal hypoxic HIF-1 alpha and HIF-2 alpha stabilization by releasing ROS to the cytosol.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                24 June 2014
                2014
                : 5
                : 149
                Affiliations
                [1] 1Laboratorio de Función y Reactividad Vascular, Programa de Fisiopatología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile Santiago, Chile
                [2] 2International Center for Andean Studies, Universidad de Chile Santiago, Chile
                [3] 3División de Obstetricia y Ginecología, Facultad de Medicina, Pontificia Universidad Católica de Chile Santiago, Chile
                [4] 4División de Pediatría, Facultad de Medicina, Pontificia Universidad Católica de Chile Santiago, Chile
                [5] 5Unidad Materno-Fetal, Hospital Clínico Universidad de Chile, Universidad de Chile Santiago, Chile
                Author notes

                Edited by: Carlos Alonso Escudero, Universidad del Bío-Bío, Chile

                Reviewed by: Brett M. Mitchell, Texas A&M Health Science Center, USA; Carlos Alonso Escudero, Universidad del Bío-Bío, ChileMarcelo Gonzalez, Universidad de Concepción, Chile

                *Correspondence: Emilio A. Herrera, Laboratorio de Función y Reactividad Vascular, Programa de Fisiopatología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Avenida Salvador 486, Providencia, Santiago 9, Chile e-mail: eherrera@ 123456med.uchile.cl

                This article was submitted to Cardiovascular and Smooth Muscle Pharmacology, a section of the journal Frontiers in Pharmacology.

                Article
                10.3389/fphar.2014.00149
                4068002
                25009498
                bdfb1e5f-df9c-41d3-8603-b6fc009fbfef
                Copyright © 2014 Herrera, Krause, Ebensperger, Reyes, Casanello, Parra-Cordero and Llanos.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 03 April 2014
                : 06 June 2014
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 149, Pages: 10, Words: 0
                Categories
                Pharmacology
                Review Article

                Pharmacology & Pharmaceutical medicine
                hypoxia,oxidative stress,placenta,vascular dysfunction,high-altitude

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