Abstract
Fetal growth restriction (FGR) is commonly associated with perinatal morbidity and mortality. Nitric oxide (NO) deficiency increases endothelin-1 (ET-1) production, and this increased ET-1 may contribute to the pathophysiology of NO deficiency-induced FGR. Using an endothelial NO synthase knockout mouse model of FGR, we sought to determine (a) the relative importance of maternal versus conceptus (fetal and placental) NO deficiency and (b) the contribution of ET-1 to the pathogenesis of FGR in this model. Fetal growth restriction occurred both with NO-deficient conceptuses in the setting of maternal NO production and with maternal NO deficiency in the setting of NO-producing conceptuses. Placental ET-1 expression was increased in NO-deficient dams, ET receptor A (ETA) production increased in endothelial nitric oxide synthase+/− placentas, and antagonism of ETA prevented FGR. These results demonstrate that both maternal and conceptus NO deficiency can contribute to FGR and suggest a role for ETA antagonists as therapeutic agents in FGR.
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Romo A, Carceller R, Tobajas J. Intrauterine growth retardation (IUGR): epidemiology and etiology. Pediatr Endocrinol Rev. 2009;6(suppl 3):332–336.
Barker DJP. The long-term outcome of retarded fetal growth. Clin Obstet Gynecol. 1997;40(4):853–863.
Mcintire DD, Bloom SL, Casey BM, Leveno KJ. Birth weight in relation to morbidity and mortality among newborn infants. New Engl J Med. 1999;340(16):1234–1238.
Lackman F, Capewell V, Richardson B, Dasilva O, Gagnon R. The risks of spontaneous preterm delivery and perinatal mortality in relation to size at birth according to fetal versus neonatal growth standards. Am J Obstet Gynecol. 2001;184(5):946–953.
Fanaroff AA, Wright LL, Stevenson DK, et al. Very-low-birth-weight outcomes of the National Institute of Child Health and Human Development Neonatal Research Network, May 1991 through December 1992. Am J Obstet Gynecol. 1995;173(5):1423–1431.
Bernstein IM, Horbar JD, Badger GJ, Ohlsson A, Golan A. Morbidity and mortality among very-low-birth-weight neonates with intrauterine growth restriction. Am J Obstet Gynecol. 2000;182(1 pt 1):198–206.
Damodaram M, Story L, Kulinskaya E, Rutherford M, Kumar S. Early adverse perinatal complications in preterm growth-restricted fetuses. Aust N Z J Obstet Gynaecol. 2011;51(3):204–209.
Low JA, Handley-Derry MH, Burke SO, et al. Association of intrauterine fetal growth retardation and learning deficits at age 9 to 11 years. Am J Obstet Gynecol. 1992;167(6):1499–1505.
Sallout B, Walker M. The fetal origin of adult diseases. J Obstet Gynaecol. 2003;23(5):555–560.
Chernausek SD. Update: consequences of abnormal fetal growth. J Clin Endocrinol Metab. 2012;97(3):689–695.
Juul A, Almstrup K, Andersson AM, et al. Possible fetal determinants of male infertility. Nat Rev Endocrinol. 2014;10(9):553–562.
Morris NH, Sooranna SR, Learmont JG, et al. Nitric oxide synthase activities in placental tissue from normotensive, preeclamptic and growth retarded pregnancies. Br J Obstet Gynaecol. 1995;102(9):711–714.
Harvey-Wilkes KB, Nielsen HC, D’alton ME. Elevated endothelin levels are associated with increased placental resistance. Am J Obstet Gynecol. 1996;174(5):1599–1604.
Myatt L, Brewer AS, Langdon G, Brockman DE. Attenuation of the vasoconstrictor effects of thromboxane and endothelin by nitric oxide in the human fetal-placental circulation. Am J Obstet Gynecol. 1992;166(1 pt 1):224–230.
Neerhof MG, Jilling T, Synowiec S, Khan S, Thaete LG. Altered endothelin receptor binding in response to nitric oxide synthase inhibition in the pregnant rat. Reprod Sci. 2008;15(4):366–373.
Goligorsky MS, Tsukahara H, Magazine H, Andersen TT, Malik AB, Bahou WF. Termination of endothelin signaling: Role of nitric oxide. J Cell Physiol. 1994;158(3):485–494.
Huang PL, Huang Z, Mashimo H, et al. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature. 1995;377(6546):239–242.
Shesely EG, Maeda N, Kim H-S, et al. Elevated blood pressures in mice lacking endothelial nitric oxide synthase. Proc Natl Acad Sci U S A. 1996;93(23):13176–13181.
Stauss HM, Nafz B, Mrowka R, Persson PB. Blood pressure control in eNOS knock-out mice: comparison with other species under NO blockade. Acta Physiol Scand. 2000;168(1):155–160.
Quaschning T, Voss F, Relle K, et al. Lack of endothelial nitric oxide synthase promotes endothelin-induced hypertension: lessons from endothelin-1 transgenic/endothelial nitric oxide synthase knockout mice. J Am Soc Nephrol. 2007;18(3):730–740.
Hefler LA, Reyes CA, O’brien WE, Gregg AR. Perinatal development of endothelial nitric oxide synthase-deficient mice. Biol Reprod. 2001;64(2):666–673.
Van Der Heijden OWH, Essers YPG, Fazzi G, Peeters LLH, De Mey JGR, Van Eys GJJM. Uterine artery remodeling and reproductive performance are impaired in endothelial nitric oxide synthase-deficient mice. Biol Reprod. 2005;72(5):1161–1168.
Pallares P, Gonzalez-Bulnes A. Intrauterine growth retardation in endothelial nitric oxide synthase-deficient mice is established from early stages of pregnancy. Biol Reprod. 2008;78(6):1002–1006.
Thaete LG, Neerhof MG, Caplan MS. Endothelin receptor A antagonism prevents hypoxia-induced intrauterine growth restriction in the rat. Am J Obstet Gynecol. 1997; 176(1 pt 1):73–76.
Thaete LG, Neerhof MG, Silver RK. Differential effects of endothelin A and B receptor antagonism on fetal growth in normal and nitric oxide-deficient rats. J Soc Gynecol Investig. 2001;8(1):18–23.
Thaete LG, Neerhof MG. Endothelin and platelet-activating factor: significance in the pathophysiology of ischemia/reperfusion-induced fetal growth restriction in the rat. Am J Obstet Gynecol. 2006;194(5):1377–1383.
Neerhof MG, Khan S, Synowiec S, Qu X-W, Thaete LG. The significance of endothelin in platelet activating factor-induced fetal growth restriction. Reprod Sci. 2012;19(11):1175–1180.
Labonté J, Brochu I, Simard E, D’orleans-Juste P. Distinct modulation of the endothelin-1 pathway in iNOS-/- and eNOS-/- mice. Can J Physiol Pharmacol. 2008;86(8):516–525.
Wu-Wong JR, Dixon DB, Chiou WJ, et al. Pharmacology of endothelin receptor antagonists ABT-627, ABT-546, A-182086 and A-192621: in vitro studies. Clin Sci. 2002;103(suppl 48):107s–111s.
Kulandavelu S, Whiteley KJ, Qu D, Mu J, Bainbridge SA, Adamson SL. Endothelial nitric oxide synthase deficiency reduces uterine blood flow, spiral artery elongation, and placental oxygenation in pregnant mice. Hypertension. 2012;60(1):231–238.
Kulandavelu S, Whiteley KJ, Bainbridge SA, Qu D, Adamson SL. Endothelial NO synthase augments fetoplacental blood flow, placental vascularization, and fetal growth in mice. Hypertension. 2013;61(1):259–266.
Pallares P, Perez-Solana ML, Torres-Rovira L, Gonzalez-Bulnes A. Phenotypic characterization by high-resolution three-dimensional magnetic resonance imaging evidences differential effects of embryo genotype on intrauterine growth retardation in NOS3-deficient mice. Biol Reprod. 2011;84(5):866–871.
Faxén M, Nasiell J, Lunell N-O, Blanck A. Differences in mRNA expression of endothelin-1, c-fos and c-jun in placentas from normal pregnancies and pregnancies complicated with preeclampsia and/or intrauterine growth retardation. Gynecol Obstet Invest. 1997;44(2):93–96.
Schiff E, Ben-Baruch G, Peleg E, et al. Immunoreactive circulating endothelin-1 in normal and hypertensive pregnancies. Am J Obstet Gynecol. 1992;166(2):624–628.
Sventek P, Li J-S, Grove K, Deschepper CF, Schiffrin EL. Vascular structure and expression of endothelin-1 gene in L-NAME-treated spontaneously hypertensive rats. Hypertension. 1996;27(1):49–55.
Fujita K, Matsumura Y, Miyazaki Y, Takaoka M, Morimoto S. Role of endothelin-1 in hypertension induced by long-term inhibition of nitric oxide synthase. Eur J Pharmacol. 1995;280(3):311–316.
Neerhof MG, Thaete LG. Chronic NOS-inhibition-induced IUGR is associated with increased circulating endothelin-1 levels in the rat. Hypertens Pregnancy. 1997;16(2):319.
Edwards DL, Arora CP, Bui DT, Castro LC. Long-term nitric oxide blockade in the pregnant rat: effects on blood pressure and plasma levels of endothelin-1. Am J Obstet Gynecol. 1996;175(2):484–488.
Kourembanas S, Mcquillan LP, Leung GK, Faller DV. Nitric oxide regulates the expression of vasoconstrictors and growth factors by vascular endothelium under both normoxia and hypoxia. J Clin Invest. 1993;92(1):99–104.
Kelly LK, Wedgwood S, Steinhorn RH, Black SM. Nitric oxide decreases endothelin-1 secretion through the activation of soluble guanylate cyclase. Am J Physiol Lung Cell Mol Physiol. 2004;286(5):1984–1991.
Ohkita M, Takaoka M, Sugii M, Shiota Y, Nojiri R, Matsumura Y. The role of nuclear factor-kappa B in the regulation of endothelin-1 production by nitric oxide. Eur J Pharmacol. 2003;472(3):159–164.
Thompson A, Valeri CR, Lieberthal W. Endothelin receptor A blockade alters hemodynamic response to nitric oxide inhibition in rats. Am J Physiol. 1995;269(2 pt 2):h743–h748.
Maric C, Aldred GP, Antoine AM, et al. Actions of endothelin-1 on cultured rat renomedullary interstitial cells are modulated by nitric oxide. Clin Exp Pharmacol Physiol. 1999;26(5–6):392–398.
Thaete LG, Kushner DM, Dewey ER, Neerhof MG. Endothelin and the regulation of uteroplacental perfusion in nitric oxide synthase inhibition-induced fetal growth restriction. Placenta. 2005;26(2–3):242–250.
Neerhof MG, Synowiec S, Khan S, Thaete LG. Pathophysiology of chronic nitric oxide synthase inhibition-induced fetal growth restriction in the rat. Hypertens Pregnancy. 2011;30(1):28–36.
Thaete LG, Dewey ER, Neerhof MG. Endothelin and the regulation of uterine and placental perfusion in hypoxia-induced fetal growth restriction. J Soc Gynecol Investig. 2004;11(1):16–21.
Thaete LG, Khan S, Synowiec S, Dayton BD, Bauch J, Neerhof MG. Endothelin receptor antagonist has limited access to the fetal compartment during chronic maternal administration late in pregnancy. Life Sci. 2012;91(13):583–586.
Hefler LA, Tempfer CB, Moreno RM, O’brien WE, Gregg AR. Endothelial-derived nitric oxide and angiotensinogen: blood pressure and metabolism during mouse pregnancy. Am J Physiol Regul Integ Comp Physiol. 2001;280(1):r174–r182.
Shesely EG, Gilbert C, Granderson G, Carretero CD, Carretero OA, Beierwaltes WH. Nitric oxide synthase gene knockout mice do not become hypertensive during pegnancy. Am J Obstet Gynecol. 2001;185(5):1198–1203.
Kulandavelu S, Qu D, Adamson SL. Cardiovascular function in mice during normal pregnancy and in the absence of endothelial NO synthase. Hypertension. 2006;47(6):1175–1182.
Boulanger C, Lüscher TF. Release of endothelin from the porcine aorta. Inhibition by endothelium-derived nitric oxide. J Clin Invest. 1990;85(2):587–590.
Richard V, Hogie M, Clozel M, Löffler B-M, Thuillez C. In vivo evidence of an endothelin-induced vasopressor tone after inhibition of nitric oxide synthesis in rats. Circulation. 1995;91(3):771–775.
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Luo, K., Thaete, L.G. & Neerhof, M.G. Endothelin Receptor A Antagonism and Fetal Growth in Endothelial Nitric Oxide Synthase Gene Knockout Maternal and Fetal Mice. Reprod. Sci. 23, 1028–1036 (2016). https://doi.org/10.1177/1933719115625839
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DOI: https://doi.org/10.1177/1933719115625839