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The Serotonin-Immune Axis in Preeclampsia

  • Preeclampsia (VD Garovic and A Kattah, Section Editors)
  • Published:
Current Hypertension Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

To review the literature and detail the potential immune mechanisms by which hyperserotonemia may drive pro-inflammation in preeclampsia and to provide insights into potential avenues for therapeutic discovery.

Recent Findings

Preeclampsia is a severe hypertensive complication of pregnancy associated with significant maternal and fetal risk. Though it lacks any effective treatment aside from delivery of the fetus and placenta, recent work suggests that targeting serotonin systems may be one effective therapeutic avenue. Serotonin dysregulation underlies multiple domains of physiologic dysfunction in preeclampsia, including vascular hyporeactivity and excess platelet aggregation. Broadly, serotonin is increased across maternal and placental domains, driven by decreased catabolism and increased availability of tryptophan precursor. Pro-inflammation, another hallmark of the disease, may drive hyperserotonemia in preeclampsia. Interactions between immunologic dysfunction and hyperserotonemia in preeclampsia depend on multiple mechanisms, which we discuss in the present review. These include altered immune cell, kynurenine pathway metabolism, and aberrant cytokine production mechanisms, which we detail. Future work may leverage animal and in vitro models to reveal serotonin targets in the context of preeclampsia’s immune biology, and ultimately to mitigate vascular and platelet dysfunction in the disease.

Summary

Hyperserotonemia in preeclampsia drives pro-inflammation via metabolic, immune cell, and cytokine-based mechanisms. These immune mechanisms may be targeted to treat vascular and platelet endophenotypes in preeclampsia.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Gumusoglu SB, et al. Neurodevelopmental outcomes of prenatal preeclampsia exposure. Trends Neurosci. 2020;43(4):253–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sandgren JA, Santillan MK, Grobe JL. Breaking a mother’s heart: circulating antiangiogenic factors and hypertension during pregnancy correlate with specific cardiac dysfunctions. Hypertension. 2016;67(6):1119–20.

    Article  CAS  PubMed  Google Scholar 

  3. Sandgren JA, et al. Vasopressin: the missing link for preeclampsia? Am J Physiol Regul Integr Comp Physiol. 2015;309(9):R1062–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Aygun BK, et al. Posterior reversible encephalopathy syndrome in severe preeclampsia: case report and literature review. J Turk Ger Gynecol Assoc. 2010;11(4):216–9.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Maher GM, et al. Association of hypertensive disorders of pregnancy with risk of neurodevelopmental disorders in offspring: a systematic review and meta-analysis. JAMA Psychiatry. 2018;75(8):809–19.

    Article  PubMed  PubMed Central  Google Scholar 

  6. • Qiu C, et al. Preeclampsia risk in relation to maternal mood and anxiety disorders diagnosed before or during early pregnancy. Am J Hypertens. 2009;22(4):397–402 This prospective cohort study found a 2.12-fold increased risk of preeclampsia in mothers with a history of mood or anxiety disorders, even after adjusting for potential confounds such as age and body mass index. Serotonergic dysregulation is a cardinal feature of anxiety and mood disorders, which are often treated by selective serotonin reuptake inhibitors (SSRIs).

    Article  PubMed  Google Scholar 

  7. Backe J, Bussen S, Steck T. Significant decrease of maternal serum serotonin levels in singleton pregnancies complicated by the HELLP syndrome. Gynecol Endocrinol. 1997;11(6):405–9.

    Article  CAS  PubMed  Google Scholar 

  8. Gujrati VR, et al. Novel appearance of placental nuclear monoamine oxidase: biochemical and histochemical evidence for hyperserotonomic state in preeclampsia-eclampsia. Am J Obstet Gynecol. 1996;175(6):1543–50.

    Article  CAS  PubMed  Google Scholar 

  9. Baganz NL, Blakely RD. A dialogue between the immune system and brain, spoken in the language of serotonin. ACS Chem Neurosci. 2013;4(1):48–63.

    Article  CAS  PubMed  Google Scholar 

  10. Cornelius DC. Preeclampsia: from inflammation to immunoregulation. Clin Med Insights Blood Disord. 2018;11:1179545X17752325.

    Article  PubMed  PubMed Central  Google Scholar 

  11. V, E., V, M. Ricerche sul secreto delle cellule enterocromaffini. Boll d Soc Med-chir Pavia. 1937;51:357–63.

    Google Scholar 

  12. •• Bolte AC, van Geijn HP, Dekker GA. Pathophysiology of preeclampsia and the role of serotonin. Eur J Obstet Gynecol Reprod Biol. 2001;95(1):12–21 This review details vascular and platelet serotonin-mediated pathological mechanisms in preeclampsia, and discusses the roles of specific serotonin receptors in mediating placental and endothelial vascular function.

    Article  CAS  PubMed  Google Scholar 

  13. • Santillan MK, et al. Pregnant mice lacking indoleamine 2,3-dioxygenase exhibit preeclampsia phenotypes. Phys Rep. 2015;3(1):e12257. This paper evidences preeclampsia-like phenotypes in an IDO knockout mouse model, demonstrating the crucial role for IDO, an immune-mediated serotonin metabolic switch point, in preeclampsia pathophysiology.

  14. Frishman WH, et al. Serotonin and serotonin antagonism in cardiovascular and non-cardiovascular disease. J Clin Pharmacol. 1995;35(6):541–72.

    Article  CAS  PubMed  Google Scholar 

  15. Li Y, et al. Regulating the balance between the kynurenine and serotonin pathways of tryptophan metabolism. FEBS J. 2017;284(6):948–66.

    Article  CAS  PubMed  Google Scholar 

  16. Blaschko, H.K.F. and V. Erspamer, 5-hydroxytryptamine and related indolealkylamines. In: H. Blaschko et al. (Eds.), sub-editor: Vittorio Erspamer. Handbuch der experimentellen Pharmakologie New series (Handbook of experimental pharmacology). Berlin: Springer-Verlag; 1966. vol. 19, xx, p 928.

  17. Charnay Y, Léger L. Brain serotonergic circuitries. Dialogues Clin Neurosci. 2010;12(4):471–87.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Palazzo E, et al. Metabotropic glutamate receptor 5 and dorsal raphe serotonin release in inflammatory pain in rat. Eur J Pharmacol. 2004;492(2-3):169–76.

    Article  CAS  PubMed  Google Scholar 

  19. Houston DS, Vanhoutte PM. Serotonin and the vascular system. Role in health and disease, and implications for therapy. Drugs. 1986;31(2):149–63.

    Article  CAS  PubMed  Google Scholar 

  20. Mossner R, Lesch KP. Role of serotonin in the immune system and in neuroimmune interactions. Brain Behav Immun. 1998;12(4):249–71.

    Article  CAS  PubMed  Google Scholar 

  21. •• Herr N, Bode C, Duerschmied D. The effects of serotonin in immune cells. Front Cardiovasc Med. 2017;4:48 This comprehensive review details the many peripheral immunomodulatory roles of serotonin after its release from activated platelets, including serotonin’s role in driving T cell stimulation; neutrophil recruitment and phagocytosis; and cytokine release by monocytes, macrophages, dendritic cells, and lymphocytes. This review also contains a helpful table which outlines the various serotonin receptors and transporters/enzymes expressed by each type of immune cell.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Bonnin A, Levitt P. Fetal, maternal, and placental sources of serotonin and new implications for developmental programming of the brain. Neuroscience. 2011;197:1–7.

    Article  CAS  PubMed  Google Scholar 

  23. Hanswijk SI, et al. Gestational factors throughout fetal neurodevelopment: the serotonin link. Int J Mol Sci. 2020;21(16):5850. https://doi.org/10.3390/ijms21165850

  24. • Rosenfeld CS. Placental serotonin signaling, pregnancy outcomes, and regulation of fetal brain development. Biol Reprod. 2020;102(3):532–538. https://doi.org/10.1093/biolre/ioz204. This review outlines the autocrine and paracrine roles of serotonin in the placenta, as well as existing data that demonstrate how altered placental serotonin production and/or signaling (either pharmacologically or due to a disease state) leads to changes in offspring brain and elsewhere.

  25. Pawluski JL, Li M, Lonstein JS. Serotonin and motherhood: from molecules to mood. Front Neuroendocrinol. 2019;53:100742.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Brew O, Sullivan MH, Woodman A. Comparison of normal and pre-eclamptic placental gene expression: a systematic review with meta-analysis. PLoS One. 2016;11(8):e0161504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Harvard, T.B.I.o.M.a The Genotype-Tissue Expression (GTEx) project. Available from: gtexportal.org.

  28. Hadden C, et al. Serotonin transporter protects the placental cells against apoptosis in caspase 3-independent pathway. J Cell Physiol. 2017;232(12):3520–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gall V, et al. Platelet serotonin concentration at term pregnancy and after birth: physiologic values for Croatian population. Coll Antropol. 2011;35(3):715–8.

    CAS  PubMed  Google Scholar 

  30. Cote F, et al. Maternal serotonin is crucial for murine embryonic development. Proc Natl Acad Sci U S A. 2007;104(1):329–34.

    Article  CAS  PubMed  Google Scholar 

  31. Muller CL, et al. Impact of maternal serotonin transporter genotype on placental serotonin, fetal forebrain serotonin, and neurodevelopment. Neuropsychopharmacology. 2017;42(2):427–36.

    Article  CAS  PubMed  Google Scholar 

  32. •• Bonnin A, et al. A transient placental source of serotonin for the fetal forebrain. Nature. 2011;472(7343):347–50 This paper demonstrates that the placenta is the primary source of serotonin to the fetal forebrain, before brain serotonin systems have matured, and that placental tryptophan-serotonin metabolism is altered under conditions of maternal immune activation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Keaton SA, et al. Altered tryptophan catabolism in placentas from women with pre-eclampsia. Int J Tryptophan Res. 2019;12:1178646919840321.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Santoso DI, et al. Localization of indoleamine 2,3-dioxygenase and 4-hydroxynonenal in normal and pre-eclamptic placentae. Placenta. 2002;23(5):373–9.

    Article  CAS  PubMed  Google Scholar 

  35. Schäfer CA, et al. Changes in serotonin metabolism in pre-eclampsia. Geburtshilfe Frauenheilkd. 1996;56(8):418–22.

    Article  PubMed  Google Scholar 

  36. Lin B, Zhu S, Shao B. Changes of plasma levels of monoamines in normal pregnancy and pregnancy-induced hypertension women and their significance. Zhonghua Fu Chan Ke Za Zhi. 1996;31(11):670–2.

    CAS  PubMed  Google Scholar 

  37. Middelkoop CM, et al. Platelet-poor plasma serotonin in normal and preeclamptic pregnancy. Clin Chem. 1993;39(8):1675–8.

    Article  CAS  PubMed  Google Scholar 

  38. Zhao W, Zhao L. Determination of plasma serotonins level in patients with pregnancy induced hypertension. Zhonghua Fu Chan Ke Za Zhi. 1999;34(7):406–8.

    CAS  PubMed  Google Scholar 

  39. Ren D, Yang M, Luo Y. The change of serotonin of venous blood in pregnancy induced hypertension. Zhonghua Fu Chan Ke Za Zhi. 1997;32(1):12–4.

    CAS  PubMed  Google Scholar 

  40. Sivasubramaniam SD, et al. Monoamine oxidase expression and activity in human placentae from pre-eclamptic and normotensive pregnancies. Placenta. 2002;23(2-3):163–71.

    Article  CAS  PubMed  Google Scholar 

  41. Carrasco G, et al. Transport and metabolism of serotonin in the human placenta from normal and severely pre-eclamptic pregnancies. Gynecol Obstet Investig. 2000;49(3):150–5.

    Article  CAS  Google Scholar 

  42. Carrasco G, et al. The expression and activity of monoamine oxidase A, but not of the serotonin transporter, is decreased in human placenta from pre-eclamptic pregnancies. Life Sci. 2000;67(24):2961–9.

    Article  CAS  PubMed  Google Scholar 

  43. Bottalico B, et al. Norepinephrine transporter (NET), serotonin transporter (SERT), vesicular monoamine transporter (VMAT2) and organic cation transporters (OCT1, 2 and EMT) in human placenta from pre-eclamptic and normotensive pregnancies. Placenta. 2004;25(6):518–29.

    Article  CAS  PubMed  Google Scholar 

  44. Taniguchi K, Okatani Y, Sagara Y. Serotonin metabolism in the fetus in preeclampsia. Asia Oceania J Obstet Gynaecol. 1994;20(1):77–86.

    Article  CAS  PubMed  Google Scholar 

  45. Seto SW, et al. Role of monoamine oxidases in the exaggerated 5-hydroxytryptamine-induced tension development of human isolated preeclamptic umbilical artery. Eur J Pharmacol. 2009;605(1-3):129–37.

    Article  CAS  PubMed  Google Scholar 

  46. Ren D, Huang W, Yang M. Immunohistochemical locating and quantitative studies of 5-hydroxytryptamine and 5-hydroxytryptamine receptor in placental villi of patients with pregnancy induced hypertension. Zhonghua Fu Chan Ke Za Zhi. 1997;32(8):480–2.

    CAS  PubMed  Google Scholar 

  47. Harmon AC, et al. The role of inflammation in the pathology of preeclampsia. Clin Sci (Lond). 2016;130(6):409–19.

    Article  CAS  Google Scholar 

  48. LaMarca B, et al. Identifying immune mechanisms mediating the hypertension during preeclampsia. Am J Physiol Regul Integr Comp Physiol. 2016;311(1):R1–9.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Lokki AI, Heikkinen-Eloranta JK, Laivuori H. The immunogenetic conundrum of preeclampsia. Front Immunol. 2018;9:2630.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Pfefferkorn ER, Rebhun S, Eckel M. Characterization of an indoleamine 2,3-dioxygenase induced by gamma-interferon in cultured human fibroblasts. J Interf Res. 1986;6(3):267–79.

    Article  CAS  Google Scholar 

  51. Kim H, et al. Brain indoleamine 2,3-dioxygenase contributes to the comorbidity of pain and depression. J Clin Invest. 2012;122(8):2940–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Jackson JC, et al. Influence of serotonin on the immune response. Immunology. 1985;54(3):505–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Kushnir-Sukhov NM, et al. 5-hydroxytryptamine induces mast cell adhesion and migration. J Immunol. 2006;177(9):6422–32.

    Article  CAS  PubMed  Google Scholar 

  54. Li N, et al. Serotonin activates dendritic cell function in the context of gut inflammation. Am J Pathol. 2011;178(2):662–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Mauler M, Bode C, Duerschmied D. Platelet serotonin modulates immune functions. Hamostaseologie. 2016;36(1):11–6.

    Article  CAS  PubMed  Google Scholar 

  56. Sacramento PM, et al. Serotonin decreases the production of Th1/Th17 cytokines and elevates the frequency of regulatory CD4(+) T-cell subsets in multiple sclerosis patients. Eur J Immunol. 2018;48(8):1376–88.

    Article  CAS  PubMed  Google Scholar 

  57. Badawy AA. Tryptophan metabolism, disposition and utilization in pregnancy. Biosci Rep. 2015;35(5):e00261. https://doi.org/10.1042/BSR20150197.

  58. Cloëz-Tayarani I, et al. Differential effect of serotonin on cytokine production in lipopolysaccharide-stimulated human peripheral blood mononuclear cells: involvement of 5-hydroxytryptamine2A receptors. Int Immunol. 2003;15(2):233–40.

    Article  PubMed  CAS  Google Scholar 

  59. Bischoff SC, et al. Role of serotonin in intestinal inflammation: knockout of serotonin reuptake transporter exacerbates 2,4,6-trinitrobenzene sulfonic acid colitis in mice. Am J Physiol Gastrointest Liver Physiol. 2009;296(3):G685–95.

    Article  CAS  PubMed  Google Scholar 

  60. Lorigo M, et al. How is the human umbilical artery regulated? J Obstet Gynaecol Res. 2018;44(7):1193–201.

    Article  PubMed  Google Scholar 

  61. Wang Y, et al. Kynurenine is an endothelium-derived relaxing factor produced during inflammation. Nat Med. 2010;16(3):279–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Feng X, et al. Comparisons of vascular responses to vasoconstrictors in human placenta in preeclampsia between preterm and later term. Curr Pharm Biotechnol. 2020;21(8):727–733. https://doi.org/10.2174/1389201021666191217114111.

  63. Taniguchi K. Vasospastic action of serotonin on the umbilical artery in normal and preeclamptic patients. J Obstet Gynaecol (Tokyo 1995). 1995;21(1):37–42.

    Article  CAS  Google Scholar 

  64. 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.

    Article  CAS  PubMed  Google Scholar 

  65. Anumba DO, et al. Stimulated nitric oxide release and nitric oxide sensitivity in forearm arterial vasculature during normotensive and preeclamptic pregnancy. Am J Obstet Gynecol. 1999;181(6):1479–84.

    Article  CAS  PubMed  Google Scholar 

  66. Cruz MA, et al. Venous placental reactivity to serotonin in normal and preeclamptic gestants. Gynecol Obstet Investig. 1993;36(3):148–52.

    Article  CAS  Google Scholar 

  67. Vanhoutte P. In: V PM, editor. Serotonin and the cardiovascular system. New York: Raven Press; 1985.

    Google Scholar 

  68. Keelan JA, Mitchell MD. Cytokines, hypoxia, and preeclampsia. J Soc Gynecol Investig. 2005;12(6):385–7.

    Article  PubMed  Google Scholar 

  69. Aghajanian A, et al. Decreased inspired oxygen stimulates de novo formation of coronary collaterals in adult heart. J Mol Cell Cardiol. 2020;150:1–11.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  70. Chen YK, et al. Free and conjugated catecholamines and serotonin in canine thoracic duct lymph: effects of feeding. Am J Phys. 1993;265(2 Pt 1):E184–9.

    CAS  Google Scholar 

  71. MaassenVanDenBrink A, Centurión D, Villalón CM. Crosstalk of vascular 5-HT1 receptors with other receptors: clinical implications. Neuropharmacology. 2008;55(6):986–93.

    Article  CAS  PubMed  Google Scholar 

  72. Gupta S, et al. Functional reactivity of 5-HT receptors in human umbilical cord and maternal subcutaneous fat arteries after normotensive or pre-eclamptic pregnancy. J Hypertens. 2006;24(7):1345–53.

    Article  CAS  PubMed  Google Scholar 

  73. Vanhoenacker P, Haegeman G, Leysen JE. 5-HT7 receptors: current knowledge and future prospects. Trends Pharmacol Sci. 2000;21(2):70–7.

    Article  CAS  PubMed  Google Scholar 

  74. Irge E, et al. Evaluation of 5-HT7 receptor expression in the placentae of normal and pre-eclamptic women. Clin Exp Hypertens. 2016;38(2):189–93.

    Article  CAS  PubMed  Google Scholar 

  75. Ugun-Klusek A, et al. Reduced placental vascular reactivity to 5-hydroxytryptamine in pre-eclampsia and the status of 5HT(2A) receptors. Vasc Pharmacol. 2011;55(5-6):157–62.

    Article  CAS  Google Scholar 

  76. Oufkir T, et al. The 5-HT 2A serotonin receptor enhances cell viability, affects cell cycle progression and activates MEK-ERK1/2 and JAK2-STAT3 signalling pathways in human choriocarcinoma cell lines. Placenta. 2010;31(5):439–47.

    Article  CAS  PubMed  Google Scholar 

  77. Crispino M, Volpicelli F, Perrone-Capano C. Role of the serotonin receptor 7 in brain plasticity: from development to disease. Int J Mol Sci. 2020;21(2):505. https://doi.org/10.3390/ijms21020505.

  78. Karlsson C, et al. 5-Hydroxytryptamine contracts human uterine artery smooth muscle predominantly via 5-HT2 receptors. Hum Reprod. 1997;12(2):361–7.

    Article  CAS  PubMed  Google Scholar 

  79. Doggrell SA. The role of 5-HT on the cardiovascular and renal systems and the clinical potential of 5-HT modulation. Expert Opin Investig Drugs. 2003;12(5):805–23.

    Article  CAS  PubMed  Google Scholar 

  80. González C, et al. Serotonin-induced vasoconstriction in human placental chorionic veins: interaction with prostaglandin F2 alpha. Gynecol Obstet Investig. 1993;35(2):86–90.

    Article  Google Scholar 

  81. Steyn DW, Odendaal HJ. Randomised controlled trial of ketanserin and aspirin in prevention of pre-eclampsia. Lancet. 1997;350(9087):1267–71.

    Article  CAS  PubMed  Google Scholar 

  82. Sisti G, et al. Neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and complete blood count components in the first trimester do not predict HELLP syndrome. Medicina (Kaunas). 2019;55(6):219. https://doi.org/10.3390/medicina55060219.

  83. Stojanovska V, Zenclussen AC. Innate and adaptive immune responses in HELLP syndrome. Front Immunol. 2020;11:667.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Staff, A.C, et al. Preeclampsia and uteroplacental acute atherosis: immune and inflammatory factors. J Reprod Immunol. 2014;101-102:120–6.

    Article  CAS  Google Scholar 

  85. Sharma A, et al. 5-Hydroxytryptophan: a precursor of serotonin influences regional blood-brain barrier breakdown, cerebral blood flow, brain edema formation, and neuropathology. Int Rev Neurobiol. 2019;146:1–44.

    Article  CAS  PubMed  Google Scholar 

  86. Halaris A. Inflammation, heart disease, and depression. Curr Psychiatry Rep. 2013;15(10):400.

    Article  PubMed  Google Scholar 

  87. Santillan MK, et al. Vasopressin in preeclampsia: a novel very early human pregnancy biomarker and clinically relevant mouse model. Hypertension. 2014;64(4):852–9.

    Article  CAS  PubMed  Google Scholar 

  88. Scroggins SM, et al. Elevated vasopressin in pregnant mice induces T-helper subset alterations consistent with human preeclampsia. Clin Sci (Lond). 2018;132(3):419–36.

    Article  CAS  Google Scholar 

  89. Ferris CF, Stolberg T, Delville Y. Serotonin regulation of aggressive behavior in male golden hamsters (Mesocricetus auratus). Behav Neurosci. 1999;113(4):804–15.

    Article  CAS  PubMed  Google Scholar 

  90. Rood BD, Beck SG. Vasopressin indirectly excites dorsal raphe serotonin neurons through activation of the vasopressin1A receptor. Neuroscience. 2014;260:205–16.

    Article  CAS  PubMed  Google Scholar 

  91. Cunningham CL, Martinez-Cerdeno V, Noctor SC. Microglia regulate the number of neural precursor cells in the developing cerebral cortex. J Neurosci. 2013;33(10):4216–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Granger JP, et al. Reduced uterine perfusion pressure (RUPP) model for studying cardiovascular-renal dysfunction in response to placental ischemia. Methods Mol Med. 2006;122:383–92.

    PubMed  Google Scholar 

  93. Perschbacher KJ, et al. Regulators of G protein signaling in cardiovascular function during pregnancy. Physiol Genomics. 2018;50(8):590–604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Heximer SP, Cristillo AD, Forsdyke DR. Comparison of mRNA expression of two regulators of G-protein signaling, RGS1/BL34/1R20 and RGS2/G0S8, in cultured human blood mononuclear cells. DNA Cell Biol. 1997;16(5):589–98.

    Article  CAS  PubMed  Google Scholar 

  95. Ghavami A, et al. Differential effects of regulator of G protein signaling (RGS) proteins on serotonin 5-HT1A, 5-HT2A, and dopamine D2 receptor-mediated signaling and adenylyl cyclase activity. Cell Signal. 2004;16(6):711–21.

    Article  CAS  PubMed  Google Scholar 

  96. • Mark MD, et al. RGS2 drives male aggression in mice via the serotonergic system. Commun Biol. 2019;2:373 This paper demonstrates that brain serotonin signaling occurs via an RGS2-mediated mechanism. It shows that RGS2 expression in serotonin neurons mediates an aggressive phenotype in mice, which is correlated with serotonin neuron activity. This may explain a role for disrupted RGS2-mediated intracellular serotonin signaling in preeclampsia.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Lifschytz T, et al. Relationship between Rgs2 gene expression level and anxiety and depression-like behaviour in a mutant mouse model: serotonergic involvement. Int J Neuropsychopharmacol. 2012;15(9):1307–18.

    Article  CAS  PubMed  Google Scholar 

  98. Stein MB, et al. Influence of RGS2 on sertraline treatment for social anxiety disorder. Neuropsychopharmacology. 2014;39(6):1340–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Kvehaugen AS, et al. Hypertension after preeclampsia and relation to the C1114G polymorphism (rs4606) in RGS2: data from the Norwegian HUNT2 study. BMC Med Genet. 2014;15:28.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. •• Oliveira-Dos-Santos AJ, et al. Regulation of T cell activation, anxiety, and male aggression by RGS2. Proc Natl Acad Sci U S A. 2000;97(22):12272–7 This study demonstrates an immune role for RGS2, a regulator of G protein–coupled receptor signaling that serotonin and other molecules signal through and that may also be disrupted in preeclampsia. RGS2-deficient mice have reduced T cell proliferation and altered cytokine production, as well as altered behavioral and neurophysiological phenotypes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Iqbal M, et al. Placental drug transporters and their role in fetal protection. Placenta. 2012;33(3):137–42.

    Article  CAS  PubMed  Google Scholar 

  102. Sabolovic Rudman S, et al. Serotonin risk factors for the development of hypertension in pregnancy. Arch Gynecol Obstet. 2015;291(4):779–85.

    Article  CAS  PubMed  Google Scholar 

  103. Cooper A, Woulfe D, Kilic F. Post-translational modifications of serotonin transporter. Pharmacol Res. 2019;140:7–13.

    Article  CAS  PubMed  Google Scholar 

  104. • Farrelly LA, et al. Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3. Nature. 2019;567(7749):535 +. This study reveals a mechanism, termed “serotonylation,” by which serotonin can directly modify histones via serotonylation of glutamine to alter gene expression profiles. This is just one potential mechanism by which hyperserotonemia may alter tissue gene expression (e.g., in preeclamptic placenta).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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This work was supported by the NIH (5T32HL007121-45 to S.B.G; R01HD089940, 1P50HD103556, and 3UL1TR002537 to M.K.S.) and the American Heart Association (AHA) (18SCG34350001 to M.K.S.; 19IPL134760288 to S.M.S.).

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  1. Department of Obstetrics and Gynecology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA

    Serena Gumusoglu, Sabrina Scroggins, Donna Santillan & Mark Santillan

  2. University of Iowa College of Nursing, Iowa City, Iowa, USA

    Julie Vignato

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  1. Serena Gumusoglu
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  2. Sabrina Scroggins
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The article topic was conceived by all authors. S.B.G. performed the literature search and analysis and drafted the manuscript. All authors critically revised the work. All authors read and approved the final manuscript.

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Correspondence to Serena Gumusoglu.

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Gumusoglu, S., Scroggins, S., Vignato, J. et al. The Serotonin-Immune Axis in Preeclampsia. Curr Hypertens Rep 23, 37 (2021). https://doi.org/10.1007/s11906-021-01155-4

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