title: Heme oxygenase-1 is critically involved in placentation, spiral artery remodeling, and blood pressure regulation during murine pregnancy.
abstract: The onset of pregnancy implies the appearance of a new organ, the placenta. One main function of the placenta is to supply oxygen to the fetus via hemoproteins. In this review, we highlight the importance of the enzyme heme oxygenase-1 (HO-1) for pregnancy to be established and maintained. HO-1 expression is pivotal to promote placental function and fetal development, thus determining the success of pregnancy. The deletion of the gene Hmox1 in mice leads to inadequate remodeling of spiral arteries and suboptimal placentation followed by intrauterine growth restriction (IUGR) and fetal lethality. A partial Hmox1 deletion leads to IUGR as well, with heterozygote and wild-type fetuses being born, but Hmox1 (-/-) significantly below the expected Mendelian rate. This strong phenotype is associated with diminished number of pregnancy-protective uterine natural killer (uNK) cells. Pregnant heterozygote females develop gestational hypertension. The protective HO-1 effects on placentation and fetal growth can be mimicked by the exogenous administration of carbon monoxide (CO), a product of heme catalyzed by HO-1. CO application promotes the in situ proliferation of uNK cells, restores placentation and fetal growth, while normalizing blood pressure. Similarly, HO-1 inhibition provokes hypertension in pregnant rats. The HO-1/CO axis plays a pivotal role in sustaining pregnancy and aids in the understanding of the biology of pregnancy and reveals a promising therapeutic application in the treatment of pregnancy complications.
authors: Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg , Germany.
authors: Maria L
authors: ML
authors: Zenclussen
authors: Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg , Germany.
authors: Nadja
authors: N
authors: Linzke
authors: Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg , Germany.
authors: Anne
authors: A
authors: Schumacher
authors: Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg , Germany.
authors: Stefan
authors: S
authors: Fest
authors: Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg , Germany.
authors: Nicole
authors: N
authors: Meyer
authors: Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg , Germany.
authors: Pablo A
authors: PA
authors: Casalis
authors: Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg , Germany.
authors: Ana C
authors: AC
authors: Zenclussen
keywords: IUGR; heme oxygenase-1; implantation; placenta; pre-eclampsia; pregnancy
references: Am J Obstet Gynecol. 2003 Oct;189(4):939-43
references: 14586330
references: Nat Med. 2007 Jun;13(6):703-10
references: 17496899
references: PLoS One. 2014 Jun 25;9(6):e100873
references: 24963809
references: Reprod Sci. 2014 Jan;21(1):138-45
references: 23749761
references: J Clin Invest. 1999 Apr;103(8):R23-9
references: 10207174
references: Am J Physiol Regul Integr Comp Physiol. 2003 Dec;285(6):R1453-60
references: 14615405
references: Am J Obstet Gynecol. 2007 Apr;196 (4):396.e1-7; discussion 396.e7
references: 17403433
references: Eur J Clin Invest. 1984 Dec;14(6):431-4
references: 6441718
references: Placenta. 2007 Aug-Sep;28(8-9):951-7
references: 17560646
references: Exp Biol Med (Maywood). 2003 Jan;228(1):59-63
references: 12524474
references: J Clin Endocrinol Metab. 2000 Jun;85(6):2345-9
references: 10852475
references: J Clin Invest. 2003 Mar;111(5):649-58
references: 12618519
references: Hypertension. 2013 May;61(5):1103-10
references: 23460290
references: J Immunol. 2005 Oct 15;175(8):4875-85
references: 16210589
references: J Exp Med. 2009 May 11;206(5):1167-79
references: 19398754
references: PLoS Pathog. 2013 Jan;9(1):e1003154
references: 23382682
references: Am J Physiol Heart Circ Physiol. 2003 Mar;284(3):H853-8
references: 12578814
references: Infect Immun. 2013 Oct;81(10):3865-71
references: 23897619
references: Circulation. 2007 Apr 3;115(13):1789-97
references: 17389265
references: Endocrinology. 1991 Dec;129(6):2895-906
references: 1954876
references: Proc Natl Acad Sci U S A. 1968 Oct;61(2):748-55
references: 4386763
references: J Clin Endocrinol Metab. 2013 Oct;98(10):4123-32
references: 23979956
references: FASEB J. 2000 Jan;14 (1):208-19
references: 10627295
references: PLoS One. 2011;6(9):e25046
references: 21949846
references: Int Immunopharmacol. 2005 Jan;5(1):41-51
references: 15589458
references: Annu Rev Pharmacol Toxicol. 2010;50:323-54
references: 20055707
references: Am J Reprod Immunol. 2003 Jul;50(1):66-76
references: 14506930
references: Cell Death Dis. 2014 Mar 20;5:e1139
references: 24651442
references: J Pathol. 2011 Oct;225(2):293-304
references: 21744344
references: J Clin Invest. 2014 Nov;124(11):4926-40
references: 25295542
references: Lab Invest. 2002 Jun;82(6):687-92
references: 12065678
references: Mol Cell Biochem. 2002 May-Jun;234-235(1-2):249-63
references: 12162441
references: Nat Rev Drug Discov. 2010 Sep;9(9):728-43
references: 20811383
references: Am J Reprod Immunol. 2012 May;67(5):376-82
references: 22133191
references: Hum Reprod. 2005 Sep;20(9):2492-501
references: 15919778
references: Am J Obstet Gynecol. 2012 Jul;207(1):57.e1-9
references: 22521459
references: Science. 2005 Jun 10;308(5728):1592-4
references: 15947178
references: J Leukoc Biol. 2009 Jan;85(1):4-19
references: 18784344
references: J Clin Invest. 1998 Mar 1;101(5):949-55
references: 9486963
references: J Biol Chem. 2003 Apr 11;278(15):12605-8
references: 12538598
references: Obstet Gynecol. 2000 Mar;95(3):353-7
references: 10711543
references: Eur Heart J. 2012 May;33(9):1150-8
references: 21411816
references: Mol Hum Reprod. 2014 Jun;20(6):579-89
references: 24623738
references: Am J Obstet Gynecol. 2005 Mar;192(3):734-41
references: 15746665
references: PLoS One. 2014 Sep 09;9(9):e106502
references: 25202912
references: Am J Physiol Regul Integr Comp Physiol. 2011 Nov;301(5):R1495-500
references: 21865547
references: Am J Obstet Gynecol. 2014 Jun;210(6):542.e1-7
references: 24412113
references: FEBS Lett. 1998 Nov 13;439(1-2):163-7
references: 9849899
references: Nat Med. 2001 Jun;7(6):693-8
references: 11385506
references: Hypertension. 2014 May;63(5):e118-9
references: 24591337
references: Br J Obstet Gynaecol. 1991 Sep;98 (9):871-9
references: 1911605
references: Obstet Gynecol. 2006 Nov;108(5):1145-52
references: 17077236
references: Annu Rev Physiol. 2007;69:69-85
references: 17014365
references: Am J Obstet Gynecol. 1999 Oct;181(4):1026-35
references: 10521771
references: Hypertension. 2014 Mar;63(3):580-8
references: 24366077
references: J Reprod Immunol. 2006 Feb;69(1):35-52
references: 16386310
references: Curr Opin Pharmacol. 2009 Aug;9(4):482-9
references: 19586801
references: Nat Med. 2000 Apr;6(4):422-8
references: 10742149
references: Front Pharmacol. 2014 Jul 01;5:155
references: 25071574
references: Obstet Gynecol. 1998 Aug;92(2):306-8
references: 9699772
references: Biol Reprod. 1998 Dec;59(6):1540-8
references: 9828203
references: Antioxid Redox Signal. 2002 Apr;4(2):229-40
references: 12006174
references: FASEB J. 2001 May;15(7):1158-68
references: 11344084
references: Mol Med. 2000 May;6(5):391-409
references: 10952020
references: J Exp Med. 2000 Oct 2;192(7):1015-26
references: 11015442
references: FASEB J. 2012 Dec;26(12):4876-85
references: 22919072
references: Placenta. 2009 Oct;30(10 ):861-8
references: 19699520
references: Med Hypotheses. 2005;64(1):17-27
references: 15533604
references: Obstet Gynecol. 2013 Feb;121(2 Pt 1):349-53
references: 23344286
references: Placenta. 2005 Feb-Mar;26(2-3):201-9
references: 15708121
references: Semin Perinatol. 2014 Dec;38(8):523-7
references: 25315293
references: Am J Hypertens. 2013 Jul;26(7):924-30
references: 23553216
references: Pediatr Res. 2005 May;57(5 Pt 2):1R-7R
references: 15817508
references: Annu Rev Physiol. 2002;64:69-92
references: 11826264
references: Med Gas Res. 2012 Feb 20;2(1):4
references: 22348450
references: Trends Mol Med. 2009 Feb;15(2):50-8
references: 19162549
references: Development. 2002 Jun;129(12 ):2879-89
references: 12050136
references: Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10919-24
references: 9380735
references: FASEB J. 2012 Sep;26(9):3715-27
references: 22645245
references: J Matern Fetal Neonatal Med. 2004 Jan;15(1):44-50
references: 15101611
references: Nat Med. 1998 Sep;4(9):1073-7
references: 9734404
references: Front Endocrinol (Lausanne). 2014 Mar 13;5:32
references: 24659985
references: Nat Rev Genet. 2006 Mar;7(3):185-99
references: 16485018
references: Front Biosci. 2007 Jan 01;12:2471-83
references: 17127256
references: Parasitol Int. 2014 Feb;63(1):254-9
references: 23845789
references: Microb Pathog. 2008 Aug;45(2):105-9
references: 18501554
references: Am J Reprod Immunol. 2012 Aug;68(2):128-37
references: 22672658
references: Thromb Res. 2011 Feb;127 Suppl 3:S72-5
references: 21262447