Mice lacking endothelial nitric oxide synthase (eNOS−/−) or catechol-O-methyl transferase (COMT−/−) exhibit a preeclampsia-like phenotype and fetal growth restriction. We hypothesized that a hypoxic insult would result in a more severe phenotype. Pregnant eNOS−/−, COMT−/− and control (C57BL/6J) mice were randomized to hypoxic (10.5% O2) or normal conditions (20.9% O2) from gestational day 10.5 to 18.5. Hypoxia increased the blood pressure in all genotypes and proteinuria in C57BL/6J and eNOS−/− mice. Fetal survival was significantly reduced following hypoxia, particularly in eNOS−/− mice. Birth weight was decreased in both C57BL/6J and COMT−/− mice. Placentas from COMT−/− mice demonstrated increased peroxynitrite. Despite similar hypoxia-induced effects on maternal blood pressure and proteinuria, eNOS−/− embryos have a decreased tolerance to hypoxia. Compared to C57BL/6J, COMT−/− mice exhibited less severe changes in proteinuria and fetal growth when exposed to prenatal hypoxia. This relative resistance to prenatal hypoxia was associated with a significant increase in placental levels of peroxynitrite.
LewisG. The Confidential Enquiry into Maternal and Child Health (CEMACH). Saving Mothers' Lives: Reviewing maternal deaths to make motherhood safer—2003-2005. The seventh report on confidential enquiries into maternal deaths in the United Kingdom. London: CEMACH; 2007.
2.
KuklinaEVAyalaCCallaghanWM. Hypertensive disorders and severe obstetric morbidity in the United States. Obstet Gynecol. 2009;113(6):1299–1306.
KhanKSWojdylaDSayLGülmezogluAMVan LookPF. WHO analysis of causes of maternal death: a systematic review. Lancet. 2006;367(9516):1066–1074.
5.
FacchinettiFAlbericoSBenedettoC. A multicenter, case-control study on risk factors for antepartum stillbirth. J Matern Fetal Neonatal Med. 2011;24(3):407–410.
HarringtonKCooperDLeesCHecherKCampbellS. Doppler ultrasound of the uterine arteries: the importance of bilateral notching in the prediction of pre-eclampsia, placental abruption or delivery of a small-for-gestational-age baby. Ultrasound Obstet Gynecol. 1996;7(3):182–188.
8.
MooreRJStrachanBKTylerDJ.. In utero perfusing fraction maps in normal and growth restricted pregnancy measured using IVIM echo-planar MRI. Placenta. 2000;21(7):726–732.
9.
MooreRJOngSSTylerDJ. Spiral artery blood volume in normal pregnancies and those compromised by pre-eclampsia. NMR Biomed. 2008;21(4):376–380.
10.
NeilsonJPAlfirevicZ. Doppler ultrasound for fetal assessment in high risk pregnancies. Cochrane Database Syst Rev. 2000;(2):CD000073.
11.
RegnaultTRde VrijerBGalanHL. Development and mechanisms of fetal hypoxia in severe fetal growth restriction. Placenta. 2007;28(7):714–723.
12.
MillsTAWareingMShennanAHPostonLBakerPNGreenwoodSL. Acute and chronic modulation of placental chorionic plate artery reactivity by reactive oxygen species. Free Radic Biol Med. 2009;47(2):159–166.
13.
RedmanCWSargentIL. Placental stress and pre-eclampsia: a revised view. Placenta. 2009;30(suppl A):S38–S42.
14.
KulandaveluSQuDAdamsonSL. Cardiovascular function in mice during normal pregnancy and in the absence of endothelial NO synthase. Hypertension. 2006;47(6):1175–1182.
15.
StanleyJLAnderssonIJHirtCJ. Effect of the anti-oxidant tempol on fetal growth in a mouse model of fetal growth restriction. Biol Reprod. 2012;87(1):1–8.
16.
StanleyJLAnderssonIJPoudelR.. Sildenafil citrate rescues fetal growth in the catechol-o-methyl transferase knockout mouse model. Hypertension. 2012;59(5):1021–1028.
17.
KanasakiKPalmstenKSugimotoH. Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia. Nature. 2008;453(7198):1117–1121.
18.
ChelbiSTVaimanD. Genetic and epigenetic factors contribute to the onset of preeclampsia. Mol Cell Endocrinol. 2008;282(1-2):120–129.
19.
NelissenECvan MontfoortAPDumoulinJC. Epigenetics and the placenta. Hum Reprod Update. 2011;17(3):397–417.
20.
KalkunteSNeversTNorrisWE. Vascular IL-10: a protective role in preeclampsia. J Reprod Immunol. 2011;88(2):165–169.
21.
LaiZKalkunteSSharmaS. A critical role of interleukin-10 in modulating hypoxia-induced preeclampsia-like disease in mice. Hypertension. 2011;57(3):505–514.
22.
Rueda-ClausenCFMortonJSDavidgeST. Effects of hypoxia-induced intrauterine growth restriction on cardiopulmonary structure and function during adulthood. Cardiovasc Res. 2009;81(4):713–722.
ChackoBKReilyCSrivastavaA. Prevention of diabetic nephropathy in Ins2(+/)(AkitaJ) mice by the mitochondria-targeted therapy MitoQ. Biochem J. 2010;432(1):9–19.
25.
MuJAdamsonSL. Developmental changes in hemodynamics of uterine artery, utero- and umbilicoplacental, and vitelline circulations in mouse throughout gestation. Am J Physiol Heart Circ Physiol. 2006;291(3):H1421–H1428.
26.
AnderssonIJSankaralingamSDavidgeST. Restraint stress up-regulates lectin-like oxidized low-density lipoprotein receptor-1 in aorta of apolipoprotein E-deficient mice. Stress. 2010;13(5):454–460.
27.
Rueda-ClausenCFMortonJSLopaschukGDDavidgeST. Long-term effects of intrauterine growth restriction on cardiac metabolism and susceptibility to ischaemia/reperfusion. Cardiovasc Res. 2011;90(2):285–294.
28.
HungTHSkepperJNCharnock-JonesDSBurtonGJ. Hypoxia-reoxygenation: a potent inducer of apoptotic changes in the human placenta and possible etiological factor in preeclampsia. Circ Res. 2002;90(12):1274–1281.
29.
LackmanFCapewellVGagnonRRichardsonB. Fetal umbilical cord oxygen values and birth to placental weight ratio in relation to size at birth. Am J Obstet Gynecol. 2001;185(3):674–682.
30.
van der HeijdenOWEssersYPFazziGPeetersLLDe MeyJGvan EysGJ. Uterine artery remodelling and reproductive performance are impaired in endothelial nitric oxide synthase-deficient mice. Biol Reprod. 2005;72(5):1161–1168.
31.
GarveyDJVaccariATimirasPS. Developmental profiles of catecholaminergic enzymes in adrenals of perinatal rats: effect of a hypoxic environment. Horm Metab Res. 1980;12(7):318–322.
32.
StanchevaSGeorgievVAlovaLGetovaD. Effects of angiotensin II on brain monoamine oxidase activity in non-hypoxic and hypoxic mice. Acta Physiol Pharmacol Bulg. 1996;22(1):27–30.
33.
BurtonGJ. Oxygen, the Janus gas; its effects on human placental development and function. J Anat. 2009;215(1):27–35.
34.
MacaraLKingdomJCKaufmannP. Structural analysis of placental terminal villi from growth-restricted pregnancies with abnormal umbilical artery Doppler waveforms. Placenta. 1996;17(1):37–48.
35.
TomlinsonTMGarbowJRAndersonJR. Magnetic resonance imaging of hypoxic injury to the murine placenta. Am J Physiol Regul Integr Comp Physiol. 2010;298(2):R312–R319.
36.
RedmanCWSargentIL. Placental debris, oxidative stress and pre-eclampsia. Placenta. 2000;21(7):597–602.
37.
HubelCA. Oxidative stress in the pathogenesis of preeclampsia. Proc Soc Exp Biol Med. 1999;222(3):222–235.
38.
WebsterBMStanleyJLRueda-ClausenCF. Effect of sildenafil citrate within the placenta: a possible mechanism for the amelioration of fetal growth restriction. Reprod Sci. 2012;19(suppl 3):390A.
39.
PisaneschiSStriginiFASanchezAM. Compensatory feto-placental upregulation of the nitric oxide system during fetal growth restriction. PLoS One. 2012;7(9):e45294.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
