Human Placental Vascular Reactivity in Health and Disease: Implications for the Treatment of Pre-eclampsia

Author(s): Emilie Hitzerd*, Michelle Broekhuizen, Rugina I. Neuman, Katrina M. Mirabito Colafella, Daphne Merkus, Sam Schoenmakers, Sinno H.P. Simons, Irwin K.M. Reiss, A.H. Jan Danser.

Journal Name: Current Pharmaceutical Design

Volume 25 , Issue 5 , 2019


Adequate development of the placenta is essential for optimal pregnancy outcome. Pre-eclampsia (PE) is increasingly recognized to be a consequence of placental dysfunction and can cause serious maternal and fetal complications during pregnancy. Furthermore, PE increases the risk of neonatal problems and has been shown to be a risk factor for cardiovascular disease of the mother later in life. Currently, there is no adequate treatment for PE, mainly because its multifactorial pathophysiology remains incompletely understood. It originates in early pregnancy with abnormal placentation and involves a cascade of dysregulated systems in the placental vasculature. To investigate therapeutic strategies it is essential to understand the regulation of vascular reactivity and remodeling of blood vessels in the placenta. Techniques using human tissue such as the ex vivo placental perfusion model provide insight in the vasoactive profile of the placenta, and are essential to study the effects of drugs on the fetal vasculature. This approach highlights the different pathways that are involved in the vascular regulation of the human placenta, changes that occur during PE and the importance of focusing on restoring these dysfunctional systems when studying treatment strategies for PE.

Keywords: Placenta, pre-eclampsia, vascular reactivity, perfusion, vasculature, vasoconstriction, vasodilation.

Gude NM, Roberts CT, Kalionis B, King RG. Growth and function of the normal human placenta. Thromb Res 2004; 114(5-6): 397-407.
Duley L. The global impact of pre-eclampsia and eclampsia. Semin Perinatol 2009; 33(3): 130-7.
Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet 2010; 376(9741): 631-44.
Lees C, Marlow N, Arabin B, et al. Perinatal morbidity and mortality in early-onset fetal growth restriction: Cohort outcomes of the trial of randomized umbilical and fetal flow in Europe (TRUFFLE). Ultrasound Obstet Gynecol 2013; 42(4): 400-8.
van der Merwe JL, Hall DR, Wright C, Schubert P, Grové D. Are early and late preeclampsia distinct subclasses of the disease--what does the placenta reveal? Hypertens Pregnancy 2010; 29(4): 457-67.
Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ 2007; 335(7627): 974.
Newstead J, von Dadelszen P, Magee LA. Preeclampsia and future cardiovascular risk. Expert Rev Cardiovasc Ther 2007; 5(2): 283-94.
Jayet PY, Rimoldi SF, Stuber T, et al. Pulmonary and systemic vascular dysfunction in young offspring of mothers with preeclampsia. Circulation 2010; 122(5): 488-94.
Mourani PM, Abman SH. Pulmonary vascular disease in bronchopulmonary dysplasia: pulmonary hypertension and beyond. Curr Opin Pediatr 2013; 25(3): 329-37.
Hintz SR, Kendrick DE, Wilson-Costello DE, et al. Early-childhood neurodevelopmental outcomes are not improving for infants born at <25 weeks’ gestational age. Pediatrics 2011; 127(1): 62-70.
Meekins JW, Pijnenborg R, Hanssens M, McFadyen IR, van Asshe A. A study of placental bed spiral arteries and trophoblast invasion in normal and severe pre-eclamptic pregnancies. Br J Obstet Gynaecol 1994; 101(8): 669-74.
Roberts JM. Pathophysiology of ischemic placental disease. Semin Perinatol 2014; 38(3): 139-45.
Maynard S, Epstein FH, Karumanchi SA. Preeclampsia and angiogenic imbalance. Annu Rev Med 2008; 59: 61-78.
von Dadelszen P, Magee LA, Roberts JM. Subclassification of preeclampsia. Hypertens Pregnancy 2003; 22(2): 143-8.
Huppertz B. The critical role of abnormal trophoblast development in the etiology of preeclampsia. Curr Pharm Biotechnol 2018; 19(10): 771-80.
Brosens I, Pijnenborg R, Vercruysse L, Romero R. The “Great Obstetrical Syndromes” are associated with disorders of deep placentation. Am J Obstet Gynecol 2011; 204(3): 193-201.
Red-Horse K, Zhou Y, Genbacev O, et al. Trophoblast differentiation during embryo implantation and formation of the maternal-fetal interface. J Clin Invest 2004; 114(6): 744-54.
Ji L, Brkić J, Liu M, Fu G, Peng C, Wang YL. Placental trophoblast cell differentiation: physiological regulation and pathological relevance to preeclampsia. Mol Aspects Med 2013; 34(5): 981-1023.
Burton GJ, Watson AL, Hempstock J, Skepper JN, Jauniaux E. Uterine glands provide histiotrophic nutrition for the human fetus during the first trimester of pregnancy. J Clin Endocrinol Metab 2002; 87(6): 2954-9.
Burton GJ, Hempstock J, Jauniaux E. Oxygen, early embryonic metabolism and free radical-mediated embryopathies. Reprod Biomed Online 2003; 6(1): 84-96.
Walker DW, McLean JR. Absence of adrenergic nerves in the human placenta. Nature 1971; 229(5283): 344-5.
Wheeler T, Elcock CL, Anthony FW. Angiogenesis and the placental environment. Placenta 1995; 16(3): 289-96.
Ahmed A, Dunk C, Ahmad S, Khaliq A. Regulation of placental vascular endothelial growth factor (VEGF) and placenta growth factor (PIGF) and soluble Flt-1 by oxygen a review Placenta 2000. (21 Suppl)A: S16-24.
Szukiewicz D, Szewczyk G, Watroba M, Kurowska E, Maslinski S. Isolated placental vessel response to vascular endothelial growth factor and placenta growth factor in normal and growth-restricted pregnancy. Gynecol Obstet Invest 2005; 59(2): 102-7.
Ahmed A, Li XF, Dunk C, Whittle MJ, Rushton DI, Rollason T. Colocalisation of vascular endothelial growth factor and its Flt-1 receptor in human placenta. Growth Factors 1995; 12(3): 235-43.
Clark DE, Smith SK, Sharkey AM, Charnock-Jones DS. Localization of VEGF and expression of its receptors flt and KDR in human placenta throughout pregnancy. Hum Reprod 1996; 11(5): 1090-8.
Brownbill P, McKeeman GC, Brockelsby JC, Crocker IP, Sibley CP. Vasoactive and permeability effects of vascular endothelial growth factor-165 in the term in vitro dually perfused human placental lobule. Endocrinology 2007; 148(10): 4734-44.
Terman BI, Carrion ME, Kovacs E, Rasmussen BA, Eddy RL, Shows TB. Identification of a new endothelial cell growth factor receptor tyrosine kinase. Oncogene 1991; 6(9): 1677-83.
Rahimi N. VEGFR-1 and VEGFR-2: two non-identical twins with a unique physiognomy. Front Biosci 2006; 11: 818-29.
Nevo O, Lee DK, Caniggia I. Attenuation of VEGFR-2 expression by sFlt-1 and low oxygen in human placenta. PLoS One 2013; 8(11): e81176.
Karumanchi SA. Angiogenic factors in preeclampsia: From diagnosis to therapy. Hypertension 2016; 67(6): 1072-9.
Saleh L, van den Meiracker AH, Geensen R, et al. Soluble fms-like tyrosine kinase-1 and placental growth factor kinetics during and after pregnancy in women with suspected or confirmed pre-eclampsia. Ultrasound Obstet Gynecol 2018; 51(6): 751-7.
Ahmad S, Ahmed A. Elevated placental soluble vascular endothelial growth factor receptor-1 inhibits angiogenesis in preeclampsia. Circ Res 2004; 95(9): 884-91.
Levine RJ, Maynard SE, Qian C, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004; 350(7): 672-83.
Polliotti BM, Fry AG, Saller DN, Mooney RA, Cox C, Miller RK. Second-trimester maternal serum placental growth factor and vascular endothelial growth factor for predicting severe, early-onset preeclampsia. Obstet Gynecol 2003; 101(6): 1266-74.
Maynard SE, Min JY, Merchan J, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 2003; 111(5): 649-58.
Murphy SR, LaMarca BB, Cockrell K, Granger JP. Role of endothelin in mediating soluble fms-like tyrosine kinase 1-induced hypertension in pregnant rats. Hypertension 2010; 55(2): 394-8.
Kappers MH, Smedts FM, Horn T, et al. The vascular endothelial growth factor receptor inhibitor sunitinib causes a preeclampsia-like syndrome with activation of the endothelin system. Hypertension 2011; 58(2): 295-302.
Brownbill P, Mills TA, Soydemir DF, Sibley CP. Vasoactivity to and endogenous release of vascular endothelial growth factor in the in vitro perfused human placental lobule from pregnancies complicated by preeclampsia. Placenta 2008; 29(11): 950-5.
Nevo O, Soleymanlou N, Wu Y, et al. Increased expression of sFlt-1 in in vivo and in vitro models of human placental hypoxia is mediated by HIF-1. Am J Physiol Regul Integr Comp Physiol 2006; 291(4): R1085-93.
Jim B, Karumanchi SA. Preeclampsia: Pathogenesis, prevention, and long-term complications. Semin Nephrol 2017; 37(4): 386-97.
Burke SD, Zsengellér ZK, Khankin EV, et al. Soluble fms-like tyrosine kinase 1 promotes angiotensin II sensitivity in preeclampsia. J Clin Invest 2016; 126(7): 2561-74.
Verdonk K, Saleh L, Lankhorst S, et al. Association studies suggest a key role for endothelin-1 in the pathogenesis of preeclampsia and the accompanying renin-angiotensin-aldosterone system suppression. Hypertension 2015; 65(6): 1316-23.
Delić R, Štefanović M, Krivec Š, Weber V. Statistical regression model of standard and new laboratory markers and its usefulness in prediction of preeclampsia. J Matern Fetal Neonatal Med 2014; 27(4): 388-92.
Thadhani R, Hagmann H, Schaarschmidt W, et al. Removal of Soluble Fms-Like Tyrosine Kinase-1 by Dextran Sulfate Apheresis in Preeclampsia. J Am Soc Nephrol 2016; 27(3): 903-13.
Logue OC, Mahdi F, Chapman H, George EM, Bidwell GL III. A maternally sequestered, biopolymer-stabilized vascular endothelial growth factor (VEGF) chimera for treatment of preeclampsia. J Am Heart Assoc 2017; 6(12): 6.
Spradley FT, Tan AY, Joo WS, et al. Placental growth factor administration abolishes placental ischemia-induced hypertension. Hypertension 2016; 67(4): 740-7.
George EM, Arany M, Cockrell K, Storm MV, Stec DE, Granger JP. Induction of heme oxygenase-1 attenuates sFlt-1-induced hypertension in pregnant rats. Am J Physiol Regul Integr Comp Physiol 2011; 301(5): R1495-500.
Onda K, Tong S, Beard S, et al. Proton pump inhibitors decrease soluble fms-like tyrosine kinase-1 and soluble endoglin secretion, decrease hypertension, and rescue endothelial dysfunction. Hypertension 2017; 69(3): 457-68.
Saleh L, Samantar R, Garrelds IM, van den Meiracker AH, Visser W, Danser AHJ. Low soluble fms-like tyrosine kinase-1, endoglin, and endothelin-1 levels in women with confirmed or suspected preeclampsia using proton pump inhibitors. Hypertension 2017; 70(3): 594-600.
Cluver CA, Walker SP, Mol BW, et al. Double blind, randomised, placebo-controlled trial to evaluate the efficacy of esomeprazole to treat early onset pre-eclampsia (PIE Trial): A study protocol. BMJ Open 2015; 5(10): e008211.
Brownfoot FC, Tong S, Hannan NJ, Hastie R, Cannon P, Kaitu’u-Lino TJ. Effects of simvastatin, rosuvastatin and pravastatin on soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sENG) secretion from human umbilical vein endothelial cells, primary trophoblast cells and placenta. BMC Pregnancy Childbirth 2016; 16: 117.
Costantine MM, Cleary K. Pravastatin for the prevention of preeclampsia in high-risk pregnant women. Obstet Gynecol 2013; 121(2 Pt 1): 349-53.
Rana S, Rajakumar A, Geahchan C, et al. Ouabain inhibits placental sFlt1 production by repressing HSP27-dependent HIF-1α pathway. FASEB J 2014; 28(10): 4324-34.
Brownfoot FC, Hastie R, Hannan NJ, et al. . Metformin as a prevention and treatment for preeclampsia: Effects on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion and endothelial dysfunction Am J Obstet Gynecol 2016. 214: 356: e1--356. e15.
Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332(6163): 411-5.
Rubanyi GM, Polokoff MA. Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. Pharmacol Rev 1994; 46(3): 325-415.
Wagner OF, Christ G, Wojta J, et al. Polar secretion of endothelin-1 by cultured endothelial cells. J Biol Chem 1992; 267(23): 16066-8.
Saleh L, Verdonk K, Visser W, van den Meiracker AH, Danser AH. The emerging role of endothelin-1 in the pathogenesis of pre-eclampsia. Ther Adv Cardiovasc Dis 2016; 10(5): 282-93.
Granger JP, Spradley FT, Bakrania BA. The endothelin system: A critical player in the pathophysiology of preeclampsia. Curr Hypertens Rep 2018; 20(4): 32.
Rutherford RA, Wharton J, McCarthy A, et al. Differential localization of endothelin ETA and ETB binding sites in human placenta. Br J Pharmacol 1993; 109(2): 544-52.
Malassiné A, Cronier L, Mondon F, Mignot TM, Ferré F. Localization and production of immunoreactive endothelin-1 in the trophoblast of human placenta. Cell Tissue Res 1993; 271(3): 491-7.
Cervar M, Puerstner P, Kainer F, Desoye G. Endothelin-1 stimulates the proliferation and invasion of first trimester trophoblastic cells in vitro--a possible role in the etiology of pre-eclampsia? J Investig Med 1996; 44(8): 447-53.
Cervar M, Huppertz B, Barth S, et al. Endothelin A and B receptors change their expression levels during development of human placental villi. Placenta 2000; 21(5-6): 536-46.
Sudo N, Kamoi K, Ishibashi M, Yamaji T. Plasma endothelin-1 and big endothelin-1 levels in women with pre-eclampsia. Acta Endocrinol (Copenh) 1993; 129(2): 114-20.
Mastrogiannis DS, O’Brien WF, Krammer J, Benoit R. Potential role of endothelin-1 in normal and hypertensive pregnancies. Am J Obstet Gynecol 1991; 165(6 Pt 1): 1711-6.
Wolff K, Faxén M, Lunell NO, Nisell H, Lindblom B. Endothelin receptor type A and B gene expression in human nonpregnant, term pregnant, and preeclamptic uterus. Am J Obstet Gynecol 1996; 175(5): 1295-300.
Sand AE, Ostlund E, Andersson E, Fried G. Endothelin-induced contractions in placental arteries is mediated by both ETA- and ETB-receptors. Acta Physiol Scand 1998; 163(3): 227-34.
Haegerstrand A, Hemsén A, Gillis C, Larsson O, Lundberg JM. Endothelin: presence in human umbilical vessels, high levels in fetal blood and potent constrictor effect. Acta Physiol Scand 1989; 137(4): 541-2.
Wilkes BM, Mento PF, Hollander AM, Maita ME, Sung S, Girardi EP. Endothelin receptors in human placenta: Relationship to vascular resistance and thromboxane release. Am J Physiol 1990; 258(5 Pt 1): E864-70.
MacLean MR, Templeton AGB, McGrath JC. The influence of endothelin-1 on human foeto-placental blood vessels: A comparison with 5-hydroxytryptamine. Br J Pharmacol 1992; 106(4): 937-41.
Gallardo V, Cruz MA, Miguel P, Carrasco G, González C. Mechanisms of endothelin-1-induced contraction in isolated placental veins from normal full-term and preterm pregnancies. Gen Pharmacol 2000; 34(5): 295-301.
Mombouli JV, Le SQ, Wasserstrum N, Vanhoutte PM. Endothelins 1 and 3 and big endothelin-1 contract isolated human placental veins. J Cardiovasc Pharmacol 1993; 22(Suppl. 8): S278-81.
Napolitano M, Miceli F, Calce A, et al. Expression and relationship between endothelin-1 messenger ribonucleic acid (mRNA) and inducible/endothelial nitric oxide synthase mRNA isoforms from normal and preeclamptic placentas. J Clin Endocrinol Metab 2000; 85(6): 2318-23.
Broegger T, Andersson KE, Aalkjaer C, Forman A, Boedtkjer DB. Sensitivity to the thromboxane A2 analog U46619 varies with inner diameter in human stem villous arteries. Placenta 2016; 39: 111-5.
Epstein BJ, Anderson S. Endothelin receptor antagonists as antihypertensives: the next frontier. Expert Rev Cardiovasc Ther 2009; 7(6): 675-87.
Taylor RN, Varma M, Teng NN, Roberts JM. Women with preeclampsia have higher plasma endothelin levels than women with normal pregnancies. J Clin Endocrinol Metab 1990; 71(6): 1675-7.
Nova A, Sibai BM, Barton JR, Mercer BM, Mitchell MD. Maternal plasma level of endothelin is increased in preeclampsia. Am J Obstet Gynecol 1991; 165(3): 724-7.
George EM, Palei AC, Granger JP. Endothelin as a final common pathway in the pathophysiology of preeclampsia: Therapeutic implications. Curr Opin Nephrol Hypertens 2012; 21(2): 157-62.
Benoit C, Zavecz J, Wang Y. Vasoreactivity of chorionic plate arteries in response to vasoconstrictors produced by preeclamptic placentas. Placenta 2007; 28(5-6): 498-504.
Inayatulla A, Chemtob S, Nuwayhid B, Varma DR. Responses of placental arteries from normotensive and preeclamptic women to endogenous vasoactive agents. Am J Obstet Gynecol 1993; 168(3 Pt 1): 869-74.
Read MA, Leitch IM, Giles WB, Bisits AM, Boura ALA, Walters WAW. U46619-mediated vasoconstriction of the fetal placental vasculature in vitro in normal and hypertensive pregnancies. J Hypertens 1999; 17(3): 389-96.
Singh HJ, Rahman A, Larmie ET, Nila A. Endothelin-l in feto-placental tissues from normotensive pregnant women and women with pre-eclampsia. Acta Obstet Gynecol Scand 2001; 80(2): 99-103.
McMahon LP, Redman CW, Firth JD. Expression of the three endothelin genes and plasma levels of endothelin in pre-eclamptic and normal gestations. Clin Sci (Lond) 1993; 85(4): 417-24.
Fiore G, Florio P, Micheli L, et al. Endothelin-1 triggers placental oxidative stress pathways: putative role in preeclampsia. J Clin Endocrinol Metab 2005; 90(7): 4205-10.
Li F, Kakoki M, Smid M, et al. Causative Effects of Genetically Determined High Maternal/Fetal Endothelin-1 on Preeclampsia-Like Conditions in Mice. Hypertension 2018; 71(5): 894-903.
Faxén M, Nisell H, Kublickiene KR. Altered gene expression of endothelin-A and endothelin-B receptors, but not endothelin-1, in myometrium and placenta from pregnancies complicated by preeclampsia. Arch Gynecol Obstet 2000; 264(3): 143-9.
Dieber-Rotheneder M, Beganovic S, Desoye G, Lang U, Cervar-Zivkovic M. Complex expression changes of the placental endothelin system in early and late onset preeclampsia, fetal growth restriction and gestational diabetes. Life Sci 2012; 91(13-14): 710-5.
Ariza AC, Ponce X, González-González ME, Larrea F, Halhali A. Effects of magnesium sulphate on placental expression of endothelin 1 and its receptors in preeclampsia. Clin Biochem 2007; 40(13-14): 976-80.
Sahay AS, Jadhav AT, Sundrani DP, Wagh GN, Mehendale SS, Joshi SR. Matrix metalloproteinases-2 (MMP-2) and matrix metalloproteinases -9 (MMP-9) are differentially expressed in different regions of normal and preeclampsia placentae. J Cell Biochem 2018; 119(8): 6657-64.
Ajne G, Wolff K, Fyhrquist F, Carlström K, Hemsén-Mörtberg A, Nisell H. Endothelin converting enzyme (ECE) activity in normal pregnancy and preeclampsia. Hypertens Pregnancy 2003; 22(3): 215-24.
Alexander BT, Rinewalt AN, Cockrell KL, Massey MB, Bennett WA, Granger JP. Endothelin type a receptor blockade attenuates the hypertension in response to chronic reductions in uterine perfusion pressure. Hypertension 2001; 37(2 Pt 2): 485-9.
Clouthier DE, Hosoda K, Richardson JA, et al. Cranial and cardiac neural crest defects in endothelin-A receptor-deficient mice. Development 1998; 125(5): 813-24.
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(13-14): 583-6.
Reynolds F. Drug transfer across the term placenta. Trophoblast Research 1998; 12: 239-55.
Wang Y, Gu Y, Zhang Y, Lewis DF, Alexander JS, Granger DN. Increased chymotrypsin-like protease (chymase) expression and activity in placentas from women with preeclampsia. Placenta 2007; 28(4): 263-9.
Bosnyak S, Jones ES, Christopoulos A, Aguilar MI, Thomas WG, Widdop RE. Relative affinity of angiotensin peptides and novel ligands at AT1 and AT2 receptors. Clin Sci (Lond) 2011; 121(7): 297-303.
Colafella KM, Hilliard LM, Denton KM. Epochs in the depressor/pressor balance of the renin-angiotensin system. Clin Sci (Lond) 2016; 130(10): 761-71.
Merrill DC, Karoly M, Chen K, Ferrario CM, Brosnihan KB. Angiotensin-(1-7) in normal and preeclamptic pregnancy. Endocrine 2002; 18(3): 239-45.
Hsueh WA, Luetscher JA, Carlson EJ, Grislis G, Fraze E, McHargue A. Changes in active and inactive renin throughout pregnancy. J Clin Endocrinol Metab 1982; 54(5): 1010-6.
Brown MA, Gallery ED, Ross MR, Esber RP. Sodium excretion in normal and hypertensive pregnancy: A prospective study. Am J Obstet Gynecol 1988; 159(2): 297-307.
Chesley LC, Talledo E, Bohler CS, Zuspan FP. Vascular Reactivity to Angiotensin Ii and Norepinephrine in Pregnant Women. Am J Obstet Gynecol 1965; 91: 837-42.
Anton L, Brosnihan KB. Systemic and uteroplacental renin--angiotensin system in normal and pre-eclamptic pregnancies. Ther Adv Cardiovasc Dis 2008; 2(5): 349-62.
Gant NF, Daley GL, Chand S, Whalley PJ, MacDonald PC. A study of angiotensin II pressor response throughout primigravid pregnancy. J Clin Invest 1973; 52(11): 2682-9.
Gant NF, Worley RJ, Everett RB, MacDonald PC. Control of vascular responsiveness during human pregnancy. Kidney Int 1980; 18(2): 253-8.
Levy A, Yagil Y, Bursztyn M, Barkalifa R, Scharf S, Yagil C. ACE2 expression and activity are enhanced during pregnancy. Am J Physiol Regul Integr Comp Physiol 2008; 295(6): R1953-61.
Mirabito KM, Hilliard LM, Wei Z, et al. Role of inflammation and the angiotensin type 2 receptor in the regulation of arterial pressure during pregnancy in mice. Hypertension 2014; 64(3): 626-31.
Chen K, Merrill DC, Rose JC. The importance of angiotensin II subtype receptors for blood pressure control during mouse pregnancy. Reprod Sci 2007; 14(7): 694-704.
Carey LC, Rose JC. The midgestational maternal blood pressure decline is absent in mice lacking expression of the angiotensin II AT2 receptor. J Renin Angiotensin Aldosterone Syst 2011; 12(1): 29-35.
Takeda-Matsubara Y, Iwai M, Cui TX, et al. Roles of angiotensin type 1 and 2 receptors in pregnancy-associated blood pressure change. Am J Hypertens 2004; 17(8): 684-9.
Bharadwaj MS, Strawn WB, Groban L, et al. Angiotensin-converting enzyme 2 deficiency is associated with impaired gestational weight gain and fetal growth restriction. Hypertension 2011; 58(5): 852-8.
Irani RA, Xia Y. The functional role of the renin-angiotensin system in pregnancy and preeclampsia. Placenta 2008; 29(9): 763-71.
Granger JP, Alexander BT, Bennett WA, Khalil RA. Pathophysiology of pregnancy-induced hypertension. Am J Hypertens 2001; 14(6 Pt 2): 178S-85S.
Langer B, Grima M, Coquard C, Bader AM, Schlaeder G, Imbs JL. Plasma active renin, angiotensin I, and angiotensin II during pregnancy and in preeclampsia. Obstet Gynecol 1998; 91(2): 196-202.
Hladunewich MA, Kingdom J, Odutayo A, et al. Postpartum assessment of the renin angiotensin system in women with previous severe, early-onset preeclampsia. J Clin Endocrinol Metab 2011; 96(11): 3517-24.
Wallukat G, Homuth V, Fischer T, et al. Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor. J Clin Invest 1999; 103(7): 945-52.
AbdAlla S,Lother H, el Massiery A, Quitterer U. Increased AT(1) receptor heterodimers in preeclampsia mediate enhanced angiotensin II responsiveness. Nat Med 2001; 7(9): 1003-9.
AbdAlla S,Abdel-Baset A, Lother H, el Massiery A, Quitterer U. Mesangial AT1/B2 receptor heterodimers contribute to angiotensin II hyperresponsiveness in experimental hypertension. J Mol Neurosci 2005; 26(2-3): 185-92.
Siddiqui AH, Irani RA, Blackwell SC, Ramin SM, Kellems RE, Xia Y. Angiotensin receptor agonistic autoantibody is highly prevalent in preeclampsia: correlation with disease severity. Hypertension 2010; 55(2): 386-93.
Li X, Shams M, Zhu J, et al. Cellular localization of AT1 receptor mRNA and protein in normal placenta and its reduced expression in intrauterine growth restriction. Angiotensin II stimulates the release of vasorelaxants. J Clin Invest 1998; 101(2): 442-54.
Marques FZ, Pringle KG, Conquest A, et al. Molecular characterization of renin-angiotensin system components in human intrauterine tissues and fetal membranes from vaginal delivery and cesarean section. Placenta 2011; 32(3): 214-21.
Symonds EM, Stanley MA, Skinner SL. Production of renin by in vitro cultures of human chorion and uterine muscle. Nature 1968; 217(5134): 1152-3.
Hodari AA, Smeby R, Bumpus FM. A renin-like substance in the human placenta. Obstet Gynecol 1967; 29(3): 313-7.
Shaw KJ, Do YS, Kjos S, et al. Human decidua is a major source of renin. J Clin Invest 1989; 83(6): 2085-92.
Li C, Ansari R, Yu Z, Shah D. Definitive molecular evidence of renin-angiotensin system in human uterine decidual cells. Hypertension 2000; 36(2): 159-64.
Morgan T, Craven C, Ward K. Human spiral artery renin-angiotensin system. Hypertension 1998; 32(4): 683-7.
Skinner SL, Lumbers ER, Symonds EM. Renin concentration in human fetal and maternal tissues. Am J Obstet Gynecol 1968; 101(4): 529-33.
Paul M, Wagner J, Dzau VJ. Gene expression of the renin-angiotensin system in human tissues. Quantitative analysis by the polymerase chain reaction. J Clin Invest 1993; 91(5): 2058-64.
Wilkes BM, Krim E, Mento PF. Evidence for a functional renin-angiotensin system in full-term fetoplacental unit. Am J Physiol 1985; 249(4 Pt 1): E366-73.
Glance DG, Elder MG, Bloxam DL, Myatt L. The effects of the components of the renin-angiotensin system on the isolated perfused human placental cotyledon. Am J Obstet Gynecol 1984; 149(4): 450-4.
Bjøro K, Stray-Pedersen S. Effects of vasoactive autacoids on different segments of human umbilicoplacental vessels. Gynecol Obstet Invest 1986; 22(1): 1-6.
Tulenko TN. Regional sensitivity to vasoactive polypeptides in the human umbilicoplacental vasculature. Am J Obstet Gynecol 1979; 135(5): 629-36.
Gao Q, Tang J, Li N, et al. A novel mechanism of angiotensin II-regulated placental vascular tone in the development of hypertension in preeclampsia. Oncotarget 2017; 8(19): 30734-41.
Parisi VM, Walsh SW. Fetal placental vascular responses to prostacyclin after angiotensin II-induced vasoconstriction. Am J Physiol 1989; 257(1 Pt 1): E102-7.
Iwamoto HS, Rudolph AM. Effects of angiotensin II on the blood flow and its distribution in fetal lambs. Circ Res 1981; 48(2): 183-9.
Napolitano PG, Hoeldtke NJ, Moore KH, et al. The fetoplacental pressor effects of low-dose acetylsalicylic acid and angiotensin II in the ex vivo cotyledon model. Am J Obstet Gynecol 1997; 177(5): 1093-6.
Tulenko TN. The actions of prostaglandins and cyclo-oxygenase inhibition on the resistance vessels supplying the human fetal placenta. Prostaglandins 1981; 21(6): 1033-43.
Erkkola RU, Pirhonen JP. Flow velocity waveforms in uterine and umbilical arteries during the angiotensin II sensitivity test. Am J Obstet Gynecol 1990; 162(5): 1193-7.
Cruz MA, Domínguez A, Gallardo V, Carrasco G, Miguel P, González C. Vascular reactivity to angiotensin II and eicosanoid production in the human placenta from term and preterm pregnancy. Gynecol Obstet Invest 2000; 50(4): 247-53.
Anton L, Merrill DC, Neves LA, et al. Activation of local chorionic villi angiotensin II levels but not angiotensin (1-7) in preeclampsia. Hypertension 2008; 51(4): 1066-72.
Ito M, Itakura A, Ohno Y, et al. Possible activation of the renin-angiotensin system in the feto-placental unit in preeclampsia. J Clin Endocrinol Metab 2002; 87(4): 1871-8.
Kossenjans W, Eis A, Sahay R, Brockman D, Myatt L. Role of peroxynitrite in altered fetal-placental vascular reactivity in diabetes or preeclampsia. Am J Physiol Heart Circ Physiol 2000; 278(4): H1311-9.
Kovac CM, Howard BC, Pierce BT, Hoeldtke NJ, Calhoun BC, Napolitano PG. Fetoplacental vascular tone is modified by magnesium sulfate in the preeclamptic ex vivo human placental cotyledon. Am J Obstet Gynecol 2003; 189(3): 839-42.
Holcberg G, Sapir O, Hallak M, et al. Selective vasodilator effect of magnesium sulfate in human placenta. Am J Reprod Immunol 2004; 51(3): 192-7.
Kalenga MK, Thomas K, de Gasparo M, De Hertogh R. Determination of renin, angiotensin converting enzyme and angiotensin II levels in human placenta, chorion and amnion from women with pregnancy induced hypertension. Clin Endocrinol (Oxf) 1996; 44(4): 429-33.
Keith IM, Will JA, Weir EK. Captopril: Association with fetal death and pulmonary vascular changes in the rabbit. Proc Soc Exp Biol Med 1982; 170(3): 378-83.
Broughton Pipkin F, Turner SR, Symonds EM. Possible risk with captopril in pregnancy: some animal data. Lancet 1980; 1(8180): 1256.
Shotan A, Widerhorn J, Hurst A, Elkayam U. Risks of angiotensin-converting enzyme inhibition during pregnancy: experimental and clinical evidence, potential mechanisms, and recommendations for use. Am J Med 1994; 96(5): 451-6.
Fiocchi R, Lijnen P, Fagard R, et al. Captopril during pregnancy. Lancet 1984; 2(8412): 1153.
Millar JA, Wilson PD, Morrison N. Management of severe hypertension in pregnancy by a combined drug regimen including captopril: case report. N Z Med J 1983; 96(742): 796-8.
Boutroy MJ, Vert P, Hurault de Ligny B, Miton A. Captopril administration in pregnancy impairs fetal angiotensin converting enzyme activity and neonatal adaptation. Lancet 1984; 2(8408): 935-6.
Alwan S, Polifka JE, Friedman JM. Angiotensin II receptor antagonist treatment during pregnancy. Birth Defects Res A Clin Mol Teratol 2005; 73(2): 123-30.
Cunningham MW Jr, Castillo J, Ibrahim T, et al. AT1-AA (Angiotensin II Type 1 Receptor Agonistic Autoantibody) Blockade Prevents Preeclamptic Symptoms in Placental Ischemic Rats. Hypertension 2018; 71(5): 886-93.
Neuman R, Danser AHJ. Autoantibodies against angiotensin and adrenergic receptors: more than a biomarker? Clin Sci (Lond) 2018; 132(1): 127-30.
Brock TG, McNish RW, Peters-Golden M. Arachidonic acid is preferentially metabolized by cyclooxygenase-2 to prostacyclin and prostaglandin E2. J Biol Chem 1999; 274(17): 11660-6.
Moncada S, Vane JR. Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2, and prostacyclin. Pharmacol Rev 1978; 30(3): 293-331.
Wilhelmsson L, Wikland M, Wiqvist N. PGH2, TxA2 and PGI2 have potent and differentiated actions on human uterine contractility. Prostaglandins 1981; 21(2): 277-86.
Jogee M, Myatt L, Moore P, Elder MG. Prostacyclin production by human placental cells in short-term culture. Placenta 1983; 4(3): 219-30.
Jeremy JY, Barradas MA, Craft IL, Mikhailidis DP, Dandona P. Does human placenta produce prostacyclin? Placenta 1985; 6(1): 45-52.
Nelson DM, Walsh SW. Thromboxane and prostacyclin production by different compartments of the human placental villus. J Clin Endocrinol Metab 1989; 68(3): 676-83.
Ekblad U. The effect of oxytocin and betamimetic stimulation on prostaglandin release in perfused human fetal placenta. Eur J Obstet Gynecol Reprod Biol 1986; 23(3-4): 153-8.
Howarth SR, Vallance P, Wilson CA. Role of thromboxane A2 in the vasoconstrictor response to endothelin-1, angiotensin II and 5-hydroxytryptamine in human placental vessels. Placenta 1995; 16(8): 679-89.
Goodman RP, Killam AP, Brash AR, Branch RA. Prostacyclin production during pregnancy: Comparison of production during normal pregnancy and pregnancy complicated by hypertension. Am J Obstet Gynecol 1982; 142(7): 817-22.
Downing I, Shepherd GL, Lewis PJ. Reduced prostacyclin production in pre-eclampsia. Lancet 1980; 2(8208-8209): 1374.
Bussolino F, Benedetto C, Massobrio M, Camussi G. Maternal vascular prostacyclin activity in pre-eclampsia. Lancet 1980; 2(8196): 702.
Yamaguchi M, Mori N. 6-Keto prostaglandin F1 alpha, thromboxane B2, and 13,14-dihydro-15-keto prostaglandin F concentrations of normotensive and preeclamptic patients during pregnancy, delivery, and the postpartum period. Am J Obstet Gynecol 1985; 151(1): 121-7.
Lewis DF, Canzoneri BJ, Gu Y, Zhao S, Wang Y. Maternal levels of prostacyclin, thromboxane, ICAM, and VCAM in normal and preeclamptic pregnancies. Am J Reprod Immunol 2010; 64(6): 376-83.
Walsh SW. Preeclampsia: An imbalance in placental prostacyclin and thromboxane production. Am J Obstet Gynecol 1985; 152(3): 335-40.
Wang YP, Walsh SW, Guo JD, Zhang JY. The imbalance between thromboxane and prostacyclin in preeclampsia is associated with an imbalance between lipid peroxides and vitamin E in maternal blood. Am J Obstet Gynecol 1991; 165(6 Pt 1): 1695-700.
Warso MA, Lands WE. Lipid peroxidation in relation to prostacyclin and thromboxane physiology and pathophysiology. Br Med Bull 1983; 39(3): 277-80.
Wang Y, Walsh SW. The ratio of thromboxane to prostacyclin is increased by peroxide in a dose-dependent manner, along with increased vasoconstriction in the human placenta. Hypertens Pregnancy 1998; 17: 1-11.
Walsh SW, Wang Y. Trophoblast and placental villous core production of lipid peroxides, thromboxane, and prostacyclin in preeclampsia. J Clin Endocrinol Metab 1995; 80(6): 1888-93.
Johnson RD, Sadovsky Y, Graham C, et al. The expression and activity of prostaglandin H synthase-2 is enhanced in trophoblast from women with preeclampsia. J Clin Endocrinol Metab 1997; 82(9): 3059-62.
Wang YP, Walsh SW, Guo JD, Zhang JY. Maternal levels of prostacyclin, thromboxane, vitamin E, and lipid peroxides throughout normal pregnancy. Am J Obstet Gynecol 1991; 165(6 Pt 1): 1690-4.
Howard RB, Hosokawa T, Maguire MH. Pressor and depressor actions of prostanoids in the intact human fetoplacental vascular bed. Prostaglandins Leukot Med 1986; 21(3): 323-30.
Higgins LE, Rey de Castro N, Addo N, et al. Placental features of late-onset adverse pregnancy outcome. PLoS One 2015; 10(6): e0129117.
Hull AD, White CR, Pearce WJ. Endothelium-derived relaxing factor and cyclic GMP-dependent vasorelaxation in human chorionic plate arteries. Placenta 1994; 15(4): 365-75.
Mills TA, Baker PN, Wareing M. The effect of mode of delivery on placental chorionic plate vascular reactivity. Hypertens Pregnancy 2007; 26(2): 201-10.
Wareing M, Crocker IP, Warren AY, Taggart MJ, Baker PN. Characterization of small arteries isolated from the human placental chorionic plate. Placenta 2002; 23(5): 400-9.
Clifton VL, Read MA, Leitch IM, et al. Corticotropin-releasing hormone-induced vasodilatation in the human fetal-placental circulation: involvement of the nitric oxide-cyclic guanosine 3′,5′-monophosphate-mediated pathway. J Clin Endocrinol Metab 1995; 80(10): 2888-93.
Abramowicz JS, Phillips DB, Jessee LN, Levene H, Parker KJ, Miller RK. Sonographic investigation of flow patterns in the perfused human placenta and their modulation by vasoactive agents with enhanced visualization by the ultrasound contrast agent Albunex. J Clin Ultrasound 1999; 27(9): 513-22.
Glance DG, Elder MG, Myatt L. The actions of prostaglandins and their interactions with angiotensin II in the isolated perfused human placental cotyledon. Br J Obstet Gynaecol 1986; 93(5): 488-94.
Poston L. The control of blood flow to the placenta. Exp Physiol 1997; 82(2): 377-87.
Szukiewicz D, Maslinska D, Poppe PX, Jagus D. Increased thromboxane release in preeclampsia after serotonin-induced placental vasoconstriction. Pathophysiology 1999; 6: 193-7.
Walsh SW, Wang Y. Maternal perfusion with low-dose aspirin preferentially inhibits placental thromboxane while sparing prostacyclin. Hypertens Pregnancy 1998; 17: 203-15.
Cui Y, Zhu B, Zheng F. Low-dose aspirin at ≤16 weeks of gestation for preventing preeclampsia and its maternal and neonatal adverse outcomes: A systematic review and meta-analysis. Exp Ther Med 2018; 15(5): 4361-9.
Bujold E, Roberge S, Lacasse Y, et al. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: A meta-analysis. Obstet Gynecol 2010; 116(2 Pt 1): 402-14.
Roberge S, Nicolaides KH, Demers S, Villa P, Bujold E. Prevention of perinatal death and adverse perinatal outcome using low-dose aspirin: A meta-analysis. Ultrasound Obstet Gynecol 2013; 41(5): 491-9.
Schisterman EF, Silver RM, Lesher LL, et al. Preconception low-dose aspirin and pregnancy outcomes: results from the EAGeR randomised trial. Lancet 2014; 384(9937): 29-36.
Nørgård B, Puhó E, Czeizel AE, Skriver MV, Sørensen HT. Aspirin use during early pregnancy and the risk of congenital abnormalities: A population-based case-control study. Am J Obstet Gynecol 2005; 192(3): 922-3.
Sones JL, Cha J, Woods AK, et al. Decidual Cox2 inhibition improves fetal and maternal outcomes in a preeclampsia-like mouse model. JCI Insight 2016; 1(3): 1.
Stika CS, Gross GA, Leguizamon G, et al. A prospective randomized safety trial of celecoxib for treatment of preterm labor. Am J Obstet Gynecol 2002; 187(3): 653-60.
Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980; 288(5789): 373-6.
Johal T, Lees CC, Everett TR, Wilkinson IB. The nitric oxide pathway and possible therapeutic options in pre-eclampsia. Br J Clin Pharmacol 2014; 78(2): 244-57.
Osol G, Ko NL, Mandalà M. Altered Endothelial Nitric Oxide Signaling as a Paradigm for Maternal Vascular Maladaptation in Preeclampsia. Curr Hypertens Rep 2017; 19(10): 82.
Bisseling TM, Maria Roes E, Raijmakers MTM, Steegers EAP, Peters WHM, Smits P. N-acetylcysteine restores nitric oxide-mediated effects in the fetoplacental circulation of preeclamptic patients. Am J Obstet Gynecol 2004; 191(1): 328-33.
Choi JW, Im MW, Pai SH. Nitric oxide production increases during normal pregnancy and decreases in preeclampsia. Ann Clin Lab Sci 2002; 32(3): 257-63.
Shore VH, Wang TH, Wang CL, Torry RJ, Caudle MR, Torry DS. Vascular endothelial growth factor, placenta growth factor and their receptors in isolated human trophoblast. Placenta 1997; 18(8): 657-65.
Vuorela P, Hatva E, Lymboussaki A, et al. Expression of vascular endothelial growth factor and placenta growth factor in human placenta. Biol Reprod 1997; 56(2): 489-94.
Velicky P, Knöfler M, Pollheimer J. Function and control of human invasive trophoblast subtypes: Intrinsic vs. maternal control. Cell Adhes Migr 2016; 10(1-2): 154-62.
Gude NM, Boura ALA, King RG, et al. Evidence for inhibition by endothelium-derived relaxing factor of thromboxane A2 receptor-mediated vasoconstriction in the fetal vessels of the human perfused placenta. Placenta 1992; 13(6): 597-605.
Molnár M, Sütö T, Tóth T, Hertelendy F. Prolonged blockade of nitric oxide synthesis in gravid rats produces sustained hypertension, proteinuria, thrombocytopenia, and intrauterine growth retardation. Am J Obstet Gynecol 1994; 170(5 Pt 1): 1458-66.
Salas SP, Altermatt F, Campos M, Giacaman A, Rosso P. Effects of long-term nitric oxide synthesis inhibition on plasma volume expansion and fetal growth in the pregnant rat. Hypertension 1995; 26(6 Pt 2): 1019-23.
Crews JK, Herrington JN, Granger JP, Khalil RA. Decreased endothelium-dependent vascular relaxation during reduction of uterine perfusion pressure in pregnant rat. Hypertension 2000; 35(1 Pt 2): 367-72.
Seligman SP, Buyon JP, Clancy RM, Young BK, Abramson SB. The role of nitric oxide in the pathogenesis of preeclampsia. Am J Obstet Gynecol 1994; 171(4): 944-8.
Pimentel AM, Pereira NR, Costa CA, et al. L-arginine-nitric oxide pathway and oxidative stress in plasma and platelets of patients with pre-eclampsia. Hypertens Res 2013; 36(9): 783-8.
Eleuterio NM, Palei AC, Rangel Machado JS, Tanus-Santos JE, Cavalli RC, Sandrim VC. Relationship between adiponectin and nitrite in healthy and preeclampsia pregnancies. Clin Chim Acta 2013; 423: 112-5.
Zheng JJ, Wang HO, Huang M, Zheng FY. Assessment of ADMA, estradiol, and progesterone in severe preeclampsia. Clin Exp Hypertens 2016; 38(4): 347-51.
Germain AM, Romanik MC, Guerra I, et al. Endothelial dysfunction: A link among preeclampsia, recurrent pregnancy loss, and future cardiovascular events? Hypertension 2007; 49(1): 90-5.
Speer PD, Powers RW, Frank MP, Harger G, Markovic N, Roberts JM. Elevated asymmetric dimethylarginine concentrations precede clinical preeclampsia, but not pregnancies with small-for-gestational-age infants. Am J Obstet Gynecol 2008; 198(112): e1-7.
Corthorn J, Germain AA, Chacón C, et al. Expression of kallikrein, bradykinin b2 receptor, and endothelial nitric oxide synthase in placenta in normal gestation, preeclampsia, and placenta accreta. Endocrine 2006; 29(3): 491-9.
Smith-Jackson K, Hentschke MR, Poli-de-Figueiredo CE, et al. Placental expression of eNOS, iNOS and the major protein components of caveolae in women with pre-eclampsia. Placenta 2015; 36(5): 607-10.
Roggensack AM, Zhang Y, Davidge ST. Evidence for peroxynitrite formation in the vasculature of women with preeclampsia. Hypertension 1999; 33(1): 83-9.
Roes EM, Raijmakers MTM, Boo TM, et al. Oral N-acetylcysteine administration does not stabilise the process of established severe preeclampsia. Eur J Obstet Gynecol Reprod Biol 2006; 127(1): 61-7.
Byrne BM, Howard RB, Morrow RJ, Whiteley KJ, Adamson SL. Role of the L-arginine nitric oxide pathway in hypoxic fetoplacental vasoconstriction. Placenta 1997; 18(8): 627-34.
González C, Cruz MA, Gallardo V, et al. Nitric oxide and prostaglandin systems inhibition on the isolated perfused human placenta from normal and preeclamptic pregnancies. Gynecol Obstet Invest 1995; 40(4): 244-8.
Grunewald C, Kublickas M, Carlström K, Lunell NO, Nisell H. Effects of nitroglycerin on the uterine and umbilical circulation in severe preeclampsia. Obstet Gynecol 1995; 86(4 Pt 1): 600-4.
Ramsay B, De Belder A, Campbell S, Moncada S, Martin JF. A nitric oxide donor improves uterine artery diastolic blood flow in normal early pregnancy and in women at high risk of pre-eclampsia. Eur J Clin Invest 1994; 24(1): 76-8.
Manzur-Verástegui S, Mandeville PB, Gordillo-Moscoso A, Hernández-Sierra JF, Rodríguez-Martínez M. Efficacy of nitroglycerine infusion versus sublingual nifedipine in severe pre-eclampsia: A randomized, triple-blind, controlled trial. Clin Exp Pharmacol Physiol 2008; 35(5-6): 580-5.
Facchinetti F, Longo M, Piccinini F, Neri I, Volpe A. L-arginine infusion reduces blood pressure in preeclamptic women through nitric oxide release. J Soc Gynecol Investig 1999; 6(4): 202-7.
Neri I, Monari F, Sgarbi L, Berardi A, Masellis G, Facchinetti F. L-arginine supplementation in women with chronic hypertension: impact on blood pressure and maternal and neonatal complications. J Matern Fetal Neonatal Med 2010; 23(12): 1456-60.
Miller MR, Megson IL. Recent developments in nitric oxide donor drugs. Br J Pharmacol 2007; 151(3): 305-21.
Griggs KC, Mackey KR, McLaughlin MK. Human chorionic plate arteries lack an endothelium-dependent relaxation response. Clin Exp Hypertens Part B Hypertens Pregnancy 1991; 10: 21-33.
Zhang XQ, Kwek K, Read MA, Donoghue JF, Walters WAW. Effects of nitrovasodilators on the human fetal-placental circulation in vitro. Placenta 2001; 22(4): 337-46.
Ong SS, Crocker IP, Warren AY, Baker PN. Functional characteristics of chorionic plate placental arteries from normal pregnant women and women with pre-eclampsia. Hypertens Pregnancy 2002; 21(3): 175-83.
Galle J, Zabel U, Hübner U, et al. Effects of the soluble guanylyl cyclase activator, YC-1, on vascular tone, cyclic GMP levels and phosphodiesterase activity. Br J Pharmacol 1999; 127(1): 195-203.
Lian TY, Jiang X, Jing ZC. Riociguat: A soluble guanylate cyclase stimulator for the treatment of pulmonary hypertension. Drug Des Devel Ther 2017; 11: 1195-207.
Brownfoot FC, Tong S, Hannan NJ, et al. YC-1 reduces placental sFlt-1 and soluble endoglin production and decreases endothelial dysfunction: A possible therapeutic for preeclampsia. Mol Cell Endocrinol 2015; 413: 202-8.
Stanley JL, Andersson IJ, Poudel R, et al. Sildenafil citrate rescues fetal growth in the catechol-O-methyl transferase knockout mouse model. Hypertension 2012; 59(5): 1021-8.
Herraiz S, Pellicer B, Serra V, et al. Sildenafil citrate improves perinatal outcome in fetuses from pre-eclamptic rats. BJOG 2012; 119(11): 1394-402.
Maharaj CH, O’Toole D, Lynch T, et al. Effects and mechanisms of action of sildenafil citrate in human chorionic arteries. Reprod Biol Endocrinol 2009; 7: 34.
Walton RB, Reed LC, Estrada SM, et al. Evaluation of Sildenafil and Tadalafil for Reversing Constriction of Fetal Arteries in a Human Placenta Perfusion Model. Hypertension 2018; 72(1): 167-76.
Samangaya RA, Mires G, Shennan A, et al. A randomised, double-blinded, placebo-controlled study of the phosphodiesterase type 5 inhibitor sildenafil for the treatment of preeclampsia. Hypertens Pregnancy 2009; 28(4): 369-82.
Ganzevoort W, Alfirevic Z, von Dadelszen P, et al. STRIDER: Sildenafil Therapy In Dismal prognosis Early-onset intrauterine growth Restriction--a protocol for a systematic review with individual participant data and aggregate data meta-analysis and trial sequential analysis. Syst Rev 2014; 3: 23.
Sharp A, Cornforth C, Jackson R, et al. Maternal sildenafil for severe fetal growth restriction (STRIDER): A multicentre, randomised, placebo-controlled, double-blind trial. Lancet Child Adolesc Health 2018; 2(2): 93-102.
Hawkes N. Trial of Viagra for fetal growth restriction is halted after baby deaths. BMJ 2018; 362: k3247.
Maurer M, Bader M, Bas M, et al. New topics in bradykinin research. Allergy 2011; 66(11): 1397-406.
Erices R, Corthorn J, Lisboa F, Valdés G. Bradykinin promotes migration and invasion of human immortalized trophoblasts. Reprod Biol Endocrinol 2011; 9: 97.
Wilkes BM, Mento PF. Bradykinin-induced vasoconstriction and thromboxane release in perfused human placenta. Am J Physiol 1988; 254(6 Pt 1): E681-6.
Prentice DA, Boura AL, Gude NM, Walters WA, King RG. Changes in the biological activity of autacoids during passage through the human perfused fetoplacental lobule. Eur J Pharmacol 1987; 141(1): 79-86.
Tom B, Dendorfer A, de Vries R, Saxena PR, Jan Danser AH. Bradykinin potentiation by ACE inhibitors: A matter of metabolism. Br J Pharmacol 2002; 137(2): 276-84.
de Moura R, Lopes MA. Effects of captopril on the human foetal placental circulation: An interaction with bradykinin and angiotensin I. Br J Clin Pharmacol 1995; 39(5): 497-501.
Hoegh AM, Borup R, Nielsen FC, Sørensen S, Hviid TV. Gene expression profiling of placentas affected by pre-eclampsia. J Biomed Biotechnol 2010; 2010: 787545.
Costa de Oliveira J, Oliveira Pereira W, Bertevello PS, Vieira Cordeiro AV. Expression of bradykinin in human placenta from healthy and preeclamptic women. Acta Sci Health Sci 2017; 39: 211-7.
Rama Sastry BV, Olubadewo J, Harbison RD, Schmidt DE. Human placental cholinergic system. Occurrence, distribution and variation with gestational age of acetylcholine in human placenta. Biochem Pharmacol 1976; 25(4): 425-31.
Boura AL, Gude NM, King RG, Walters WA. Acetylcholine output and foetal vascular resistance of human perfused placental cotyleda. Br J Pharmacol 1986; 88(2): 301-6.
Tayebati SK, Sabbatini M, Zaccheo D, Amenta F. Muscarinic cholinergic receptor subtypes expression by human placenta. Neurosci Lett 1997; 221(2-3): 208-12.
Lips KS, Brüggmann D, Pfeil U, Vollerthun R, Grando SA, Kummer W. Nicotinic acetylcholine receptors in rat and human placenta. Placenta 2005; 26(10): 735-46.
Rowell PP, Sastry BV. Human placental cholinergic system: depression of the uptake of alpha-aminoisobutyric acid in isolated human placental villi by choline acetyltransferase inhibitors. J Pharmacol Exp Ther 1981; 216(2): 232-8.
Sastry BV. Human placental cholinergic system. Biochem Pharmacol 1997; 53(11): 1577-86.
Murthy NV, Melville GN, Wynter HH, Wray SR, Shantha Ram NV, Hari Haran NV. In vitro human placental perfusion studies cholinergic activity in normal subjects and in toxaemia of pregnancy. West Indian Med J 1985; 34(4): 257-60.
Satyanarayana M. A correlative review of acetylcholine synthesis in relation to histopathology of the human syncytiotrophoblast. Acta Obstet Gynecol Scand 1986; 65(6): 567-72.
Tayebati SK, Giannella M, Indraccolo SR, et al. Muscarinic cholinergic receptors and acetylcholinesterase activity in umbilical artery and vein in pregnancy-induced hypertension (pre-eclampsia). Clin Exp Hypertens 1997; 19(8): 1205-17.
Machaalani R, Ghazavi E, David RV, Hinton T, Makris A, Hennessy A. Nicotinic acetylcholine receptors (nAChR) are increased in the pre-eclamptic placenta. Hypertens Pregnancy 2015; 34(2): 227-40.
Conklin BS, Zhao W, Zhong DS, Chen C. Nicotine and cotinine up-regulate vascular endothelial growth factor expression in endothelial cells. Am J Pathol 2002; 160(2): 413-8.
Hammoud AO, Bujold E, Sorokin Y, Schild C, Krapp M, Baumann P. Smoking in pregnancy revisited: findings from a large population-based study. Am J Obstet Gynecol 2005; 192: 1856-62.
Jeyabalan A, Powers RW, Durica AR, Harger GF, Roberts JM, Ness RB. Cigarette smoke exposure and angiogenic factors in pregnancy and preeclampsia. Am J Hypertens 2008; 21(8): 943-7.
Mimura K, Tomimatsu T, Sharentuya N, et al. Nicotine restores endothelial dysfunction caused by excess sFlt1 and sEng in an in vitro model of preeclamptic vascular endothelium: A possible therapeutic role of nicotinic acetylcholine receptor (nAChR) agonists for preeclampsia. Am J Obstet Gynecol 2010; 202(464): e1-6.
Sörbo J, Jakobsson A, Norrby K. Mast-cell histamine is angiogenic through receptors for histamine1 and histamine2. Int J Exp Pathol 1994; 75(1): 43-50.
Maintz L, Schwarzer V, Bieber T, van der Ven K, Novak N. Effects of histamine and diamine oxidase activities on pregnancy: A critical review. Hum Reprod Update 2008; 14(5): 485-95.
Dubois AM, Santais MC, Foussard C, et al. Blood histamine and plasma histaminase level during human pregnancy [proceedings] Agents Actions 1977; 7(1): 112.
Liu Z, Kilburn BA, Leach RE, Romero R, Paria BC, Armant DR. Histamine enhances cytotrophoblast invasion by inducing intracellular calcium transients through the histamine type-1 receptor. Mol Reprod Dev 2004; 68(3): 345-53.
Jeong HJ, Moon PD, Kim SJ, et al. Activation of hypoxia-inducible factor-1 regulates human histidine decarboxylase expression. Cell Mol Life Sci 2009; 66(7): 1309-19.
Mills TA, Taggart MJ, Greenwood SL, Baker PN, Wareing M. Histamine-induced contraction and relaxation of placental chorionic plate arteries. Placenta 2007; 28(11-12): 1158-64.
Cruz MA, González C, Sepúlveda WH, Rudolph MI. Effect of histamine on human placental chorionic veins: interaction with serotonin. Pharmacology 1991; 42(2): 86-90.
Bertrand C, St-Louis J. Reactivities to serotonin and histamine in umbilical and placental vessels during the third trimester after normotensive pregnancies and pregnancies complicated by preeclampsia. Am J Obstet Gynecol 1999; 180(3 Pt 1): 650-9.
Sabry S, Mondon F, Ferré F, Dinh-Xuan AT. In vitro contractile and relaxant responses of human resistance placental stem villi arteries of healthy parturients: Role of endothelium. Fundam Clin Pharmacol 1995; 9(1): 46-51.
Brew OB, Sullivan MH. Localisation of mRNAs for diamine oxidase and histamine receptors H1 and H2, at the feto-maternal interface of human pregnancy. Inflamm Res 2001; 50(9): 449-52.
Nava MP, Fraile A. Effects of diamine oxidase inhibition during pregnancy in the rat. Rev Esp Fisiol 1988; 44(2): 131-5.
Woods JR Jr, Brinkman CR III, Assali NS. Fetal and neonatal cardiopulmonary response to histamine. Obstet Gynecol 1976; 48(2): 195-202.
Szukiewicz D, Szukiewicz A, Maslinska D, Poppe P, Gujski M, Olszewski M. Mast cells and histamine in intrauterine growth retardation--relation to the development of placental microvessels. Inflamm Res 1999; 48(Suppl. 1): S41-2.
Szewczyk G, Pyzlak M, Klimkiewicz J, Smiertka W, Miedzińska-Maciejewska M, Szukiewicz D. Mast cells and histamine: do they influence placental vascular network and development in preeclampsia? Mediators Inflamm 2012; 2012: 307189.
Murthi P, Wallace EM, Walker DW. Altered placental tryptophan metabolic pathway in human fetal growth restriction. Placenta 2017; 52: 62-70.
Clerck FFPD. Serotonin and amplification mechanisms in platelet reactions. Physiology (Bethesda) 1989; 4: 130-3.
Laurent L, Deroy K, St-Pierre J, Côté F, Sanderson JT, Vaillancourt C. Human placenta expresses both peripheral and neuronal isoform of tryptophan hydroxylase. Biochimie 2017; 140: 159-65.
Watts SW, Morrison SF, Davis RP, Barman SM. Serotonin and blood pressure regulation. Pharmacol Rev 2012; 64(2): 359-88.
Gonzalez C, Cruz MA, Sepulveda WH, Rudolph MI. Effects of serotonin on vascular tone of isolated human placental chorionic veins. Gynecol Obstet Invest 1990; 29(2): 88-91.
González C, Cruz MA, Gallardo V, Albornoz J, Bravo I. Serotonin-induced vasoconstriction in human placental chorionic veins: interaction with prostaglandin F2 α. Gynecol Obstet Invest 1993; 35(2): 86-90.
Reviriego J, Marín J. Effects of 5-hydroxytryptamine on human isolated placental chorionic arteries and veins. Br J Pharmacol 1989; 96(4): 961-9.
Cruz MA, Gallardo V, Miguel P, Carrasco G, González C. Mediation by 5-HT2 receptors of 5-hydroxytryptamine-induced contractions of human placental vein. Gen Pharmacol 1998; 30(4): 483-8.
Haugen G. The vasoactive effects of serotonin in normal and single umbilical artery cords in normotensive and hypertensive pregnancies. Hypertens Pregnancy 1996; 15: 39-50.
Petersen OB, Skajaa K, Svane D, Gregersen H, Forman A. The effects of dihydralazine, labetalol and magnesium sulphate on the isolated, perfused human placental cotyledon. Br J Obstet Gynaecol 1994; 101(10): 871-8.
Gude NM, King RG, Brennecke SP. Autacoid interactions in the regulation of blood flow in the human placenta. Clin Exp Pharmacol Physiol 1998; 25(9): 706-11.
Read MA, Boura ALA, Walters WAW. Effects of variation in oxygen tension on responses of the human fetoplacental vasculature to vasoactive agents in vitro. Placenta 1995; 16(8): 667-78.
Taniguchi K, Okatani Y, Sagara Y. Serotonin metabolism in the fetus in preeclampsia. Asia Oceania J Obstet Gynaecol 1994; 20(1): 77-86.
Middelkoop CM, Dekker GA, Kraayenbrink AA, Popp-Snijders C. Platelet-poor plasma serotonin in normal and preeclamptic pregnancy. Clin Chem 1993; 39(8): 1675-8.
Carrasco G, Cruz MA, Gallardo V, Miguel P, Lagos M, González C. Plasma and platelet concentration and platelet uptake of serotonin in normal and pre-eclamptic pregnancies. Life Sci 1998; 62(15): 1323-32.
Haugen G, Mellembakken J, Stray-Pedersen S. Characterization of the vasodilatatory response to serotonin in human umbilical arteries perfused in vitro. The influence of the endothelium. Early Hum Dev 1997; 47(2): 185-93.
Uguz F. Is There Any Association Between Use of Antidepressants and Preeclampsia or Gestational Hypertension?: A Systematic Review of Current Studies. J Clin Psychopharmacol 2017; 37(1): 72-7.
Carrasco G, Cruz MA, Gallardo V, Miguel P, Lagos M, González C. Plasma and platelet concentration and platelet uptake of serotonin in normal and pre-eclamptic pregnancies. Life Sci 1998; 62(15): 1323-32.
Lupattelli A, Wood M, Lapane K, Spigset O, Nordeng H. Risk of preeclampsia after gestational exposure to selective serotonin reuptake inhibitors and other antidepressants: A study from The Norwegian Mother and Child Cohort Study. Pharmacoepidemiol Drug Saf 2017; 26(10): 1266-76.
Avalos LA, Chen H, Li DK. Antidepressant medication use, depression, and the risk of preeclampsia. CNS Spectr 2015; 20(1): 39-47.
Bijvank SW, Visser W, Duvekot JJ, et al. Ketanserin versus dihydralazine for the treatment of severe hypertension in early-onset preeclampsia: A double blind randomized controlled trial. Eur J Obstet Gynecol Reprod Biol 2015; 189: 106-11.
Steyn DW, Odendaal HJ. Serotonin antagonism and serotonin antagonists in pregnancy: role of ketanserin. Obstet Gynecol Surv 2000; 55(9): 582-9.
Stone TW, Darlington LG. Endogenous kynurenines as targets for drug discovery and development. Nat Rev Drug Discov 2002; 1(8): 609-20.
Sedlmayr P, Blaschitz A, Stocker R. The role of placental tryptophan catabolism. Front Immunol 2014; 5: 230.
Chang RQ, Li DJ, Li MQ. The role of indoleamine-2,3-dioxygenase in normal and pathological pregnancies. Am J Reprod Immunol 2018; 79(4): e12786.
Blaschitz A, Gauster M, Fuchs D, et al. Vascular endothelial expression of indoleamine 2,3-dioxygenase 1 forms a positive gradient towards the feto-maternal interface. PLoS One 2011; 6(7): e21774.
Santoso DI, Rogers P, Wallace EM, Manuelpillai U, Walker D, Subakir SB. Localization of indoleamine 2,3-dioxygenase and 4-hydroxynonenal in normal and pre-eclamptic placentae. Placenta 2002; 23(5): 373-9.
Kudo Y. The role of placental indoleamine 2,3-dioxygenase in human pregnancy. Obstet Gynecol Sci 2013; 56(4): 209-16.
Wang Y, Liu H, McKenzie G, et al. Kynurenine is an endothelium-derived relaxing factor produced during inflammation. Nat Med 2010; 16(3): 279-85.
Zardoya-Laguardia P, Blaschitz A, Hirschmugl B, et al. Endothelial indoleamine 2,3-dioxygenase-1 regulates the placental vascular tone and is deficient in intrauterine growth restriction and pre-eclampsia. Sci Rep 2018; 8(1): 5488.
Sakakibara K, Feng G-G, Li J, et al. Kynurenine causes vasodilation and hypotension induced by activation of KCNQ-encoded voltage-dependent K(+) channels. J Pharmacol Sci 2015; 129(1): 31-7.
Iwahashi N, Yamamoto M, Nanjo S, Toujima S, Minami S, Ino K. Downregulation of indoleamine 2, 3-dioxygenase expression in the villous stromal endothelial cells of placentas with preeclampsia. J Reprod Immunol 2017; 119: 54-60.
Kudo Y, Boyd CA, Sargent IL, Redman CW. Decreased tryptophan catabolism by placental indoleamine 2,3-dioxygenase in preeclampsia. Am J Obstet Gynecol 2003; 188(3): 719-26.
Russell FA, King R, Smillie SJ, Kodji X, Brain SD. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev 2014; 94(4): 1099-142.
Dong YL, Vegiraju S, Chauhan M, et al. Involvement of calcitonin gene-related peptide in control of human fetoplacental vascular tone. Am J Physiol Heart Circ Physiol 2004; 286(1): H230-9.
Stevenson JC, Macdonald DW, Warren RC, Booker MW, Whitehead MI. Increased concentration of circulating calcitonin gene related peptide during normal human pregnancy. Br Med J (Clin Res Ed) 1986; 293(6558): 1329-30.
Parida SK, Schneider DB, Stoss TD, Pauly TH, McGillis JP. Elevated circulating calcitonin gene-related peptide in umbilical cord and infant blood associated with maternal and neonatal sepsis and shock. Pediatr Res 1998; 43(2): 276-82.
Thota C, Gangula PR, Dong YL, Yallampalli C. Changes in the expression of calcitonin receptor-like receptor, receptor activity-modifying protein (RAMP) 1, RAMP2, and RAMP3 in rat uterus during pregnancy, labor, and by steroid hormone treatments. Biol Reprod 2003; 69(4): 1432-7.
Schneider D, Hernández C, Farías M, Uauy R, Krause BJ, Casanello P. Oxidative stress as common trait of endothelial dysfunction in chorionic arteries from fetuses with IUGR and LGA. Placenta 2015; 36(5): 552-8.
Krause BJ, Carrasco-Wong I, Caniuguir A, Carvajal J, Farías M, Casanello P. Endothelial eNOS/arginase imbalance contributes to vascular dysfunction in IUGR umbilical and placental vessels. Placenta 2013; 34(1): 20-8.
Dong YL, Green KE, Vegiragu S, et al. Evidence for decreased calcitonin gene-related peptide (CGRP) receptors and compromised responsiveness to CGRP of fetoplacental vessels in preeclamptic pregnancies. J Clin Endocrinol Metab 2005; 90(4): 2336-43.
Yadav S, Yadav YS, Goel MM, Singh U, Natu SM, Negi MP. Calcitonin gene- and parathyroid hormone-related peptides in normotensive and preeclamptic pregnancies: A nested case-control study. Arch Gynecol Obstet 2014; 290(5): 897-903.
Yallampalli C, Dong YL, Wimalawansa SJ. Calcitonin gene-related peptide reverses the hypertension and significantly decreases the fetal mortality in pre-eclampsia rats induced by N(G)-nitro-L-arginine methyl ester. Hum Reprod 1996; 11(4): 895-9.
Gangula PR, Dong YL, Wimalawansa SJ, Yallampalli C. Infusion of pregnant rats with calcitonin gene-related peptide (CGRP)(8-37), a CGRP receptor antagonist, increases blood pressure and fetal mortality and decreases fetal growth. Biol Reprod 2002; 67(2): 624-9.
Márquez-Rodas I, Longo F, Rothlin RP, Balfagón G. Pathophysiology and therapeutic possibilities of calcitonin gene-related peptide in hypertension. J Physiol Biochem 2006; 62(1): 45-56.
Aubdool AA, Thakore P, Argunhan F, et al. A novel α-calcitonin gene-related peptide analogue protects against end-organ damage in experimental hypertension, cardiac hypertrophy, and heart failure. Circulation 2017; 136(4): 367-83.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [505 - 527]
Pages: 23
DOI: 10.2174/1381612825666190405145228
Price: $58

Article Metrics

PDF: 31
PRC: 1