All Title Author
Keywords Abstract

RAS in Pregnancy and Preeclampsia and Eclampsia

DOI: 10.1155/2012/739274

Full-Text   Cite this paper   Add to My Lib


Preeclampsia is a common disease of pregnancy characterized by the presence of hypertension and commitment of many organs, including the brain, secondary to generalized endothelial dysfunction. Its etiology is not known precisely, but it involved several factors, highlighting the renin angiotensin system (RAS), which would have an important role in the origin of multisystem involvement. This paper reviews the evidence supporting the involvement of RAS in triggering the disease, in addition to the components of this system that would be involved and how it eventually produces brain engagement. 1. Introduction Preeclampsia is a major complication of pregnancy and corresponds to a major cause of both maternal and fetal morbidity and mortality [1–3]. It is a condition that produces a compromise of many organs, including the brain causing seizures, a condition known as eclampsia [4, 5]. The pathophysiology is not well understood, but it involves different factors, such as genetic, immunological, and inflammatory [6, 7]. In recent years there is a series of studies linking the renin angiotensin system (RAS) with preeclampsia [8–10], in the sense that the alteration of this system would be involved in the pathogenesis of this disease, as this could trigger the different characteristics in this pathology, including brain involvement. 2. RAS in Normal Pregnancy RAS is a system that functions as an important regulator of blood pressure, electrolyte balance, and fluid homeostasis [11]. This system comprises the inactive peptide angiotensinogen, which is converted to angiotensin I and then the active peptide angiotensin II (Ang II) through the action of renin and angiotensin-converting enzyme (ACE) [12]. Ang II exerts its action primarily through the AT1 receptor, located widely in different tissues, including the syncytiotrophoblast [10]. During pregnancy usually occurs overexpression of many components of the RAS, both in the blood and tissues. There is an increase in plasma renin mainly by extrarenal production [13]. There is also a higher-level production of angiotensinogen liver secondary to increased circulating estrogens. ACE is the only component that has been shown to decrease during normal pregnancy, but equally there is a higher plasma concentration of Ang II [8, 13]. There is an upregulation of RAS components during normal pregnancy, but there is also a decrease in sensitivity to Ang II, whereby these women are resistant to the pressor effect of this molecule, requiring twice Ang II by intravenous infusion compared with nonpregnant women to achieve a


[1]  B. Sibai, G. Dekker, and M. Kupferminc, “Pre-eclampsia,” The Lancet, vol. 365, no. 9461, pp. 785–799, 2005.
[2]  L. Duley, “Maternal mortality associated with hypertensive disorders of pregnancy in Africa, Asia, Latin America and the Caribbean,” British Journal of Obstetrics and Gynaecology, vol. 99, no. 7, pp. 547–553, 1992.
[3]  L. Duley, “The global impact of pre-eclampsia and eclampsia,” Seminars in Perinatology, vol. 33, no. 3, pp. 130–137, 2009.
[4]  E. R. Norwitz, C. D. Hsu, and J. T. Repke, “Acute complications of preeclampsia,” Clinical Obstetrics and Gynecology, vol. 45, no. 2, pp. 308–329, 2002.
[5]  G. G. Zeeman, “Neurologic complications of pre-eclampsia,” Seminars in Perinatology, vol. 33, no. 3, pp. 166–172, 2009.
[6]  J. M. Roberts and D. W. Cooper, “Pathogenesis and genetics of pre-eclampsia,” The Lancet, vol. 357, no. 9249, pp. 53–56, 2001.
[7]  J. L. James, G. S. Whitley, and J. E. Cartwright, “Pre-eclampsia: fitting together the placental, immune and cardiovascular pieces,” Journal of Pathology, vol. 221, no. 4, pp. 363–378, 2010.
[8]  D. M. Shah, “Role of the renin-angiotensin system in the pathogenesis of preeclampsia,” American Journal of Physiology, vol. 288, no. 4, pp. F614–F625, 2005.
[9]  R. A. Irani and Y. Xia, “The functional role of the renin-angiotensin system in pregnancy and preeclampsia,” Placenta, vol. 29, no. 9, pp. 763–771, 2008.
[10]  R. A. Irani and Y. Xia, “Renin angiotensin signaling in normal pregnancy and preeclampsia,” Seminars in Nephrology, vol. 31, no. 1, pp. 47–58, 2011.
[11]  D. M. Shah, “The role of RAS in the pathogenesis of preeclampsia,” Current Hypertension Reports, vol. 8, no. 2, pp. 144–152, 2005.
[12]  W. R. Welches, K. B. Brosnihan, and C. M. Ferrario, “A comparison of the properties and enzymatic activities of three angiotensin processing enzymes: angiotensin converting enzyme, prolyl endopeptidase and neutral endopeptidase 24.11,” Life Sciences, vol. 52, no. 18, pp. 1461–1480, 1993.
[13]  L. Anton and K. B. Brosnihan, “Systemic and uteroplacental renin-angiotensin system in normal and pre-eclamptic pregnancies,” Therapeutic Advances in Cardiovascular Disease, vol. 2, no. 5, pp. 349–362, 2008.
[14]  R. Abdul-Karim and N. S. Assali, “Pressor response to angiotensin in pregnant and non-pregnant women,” American Journal of Obstetrics and Gynecology, vol. 82, pp. 246–251, 1961.
[15]  S. AbdAlla, H. Lother, A. El Massiery, and U. Quitterer, “Increased AT1 receptor heterodimers in preeclampsia mediate enhanced angiotensin II responsiveness,” Nature Medicine, vol. 7, no. 9, pp. 1003–1009, 2001.
[16]  K. B. Brosnihan, L. A. A. Neves, L. Anton, J. Joyner, G. Valdes, and D. C. Merrill, “Enhanced expression of Ang-(1–7) during pregnancy,” Brazilian Journal of Medical and Biological Research, vol. 37, no. 8, pp. 1255–1262, 2004.
[17]  T. Morgan, C. Craven, J. M. Lalouel, and K. Ward, “Angiotensinogen Thr235 variant is associated with abnormal physiologic change of the uterine spiral arteries in first-trimester decidua,” American Journal of Obstetrics and Gynecology, vol. 180, no. 1 I, pp. 95–102, 1999.
[18]  L. Poston, “Endothelial dysfunction in pre-eclampsia,” Pharmacological Reports, vol. 58, pp. 69–74, 2006.
[19]  C. W. G. Redman and I. L. Sargent, “Placental stress and pre-eclampsia: a revised view,” Placenta, vol. 30, pp. S38–S42, 2009.
[20]  P. Kaufmann, S. Black, and B. Huppertz, “Endovascular trophoblast invasion: implications for the pathogenesis of intrauterine growth retardation and preeclampsia,” Biology of Reproduction, vol. 69, no. 1, pp. 1–7, 2003.
[21]  ACOG Committee on Obstetric Practice, “ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002. American college of obstetricians and gynecologists,” International Journal of Gynecology and Obstetrics, vol. 77, no. 1, pp. 67–75, 2002.
[22]  C. W. Redman and I. L. Sargent, “Latest advances in understanding preeclampsia,” Science, vol. 308, no. 5728, pp. 1592–1594, 2005.
[23]  V. Chaddha, S. Viero, B. Huppertz, and J. Kingdom, “Developmental biology of the placenta and the origins of placental insufficiency,” Seminars in Fetal and Neonatal Medicine, vol. 9, no. 5, pp. 357–369, 2004.
[24]  C. W. G. Redman and I. L. Sargent, “Pre-eclampsia, the placenta and the maternal systemic inflammatory response—a review,” Placenta, vol. 24, pp. S21–S27, 2003.
[25]  F. Bernardi, F. Guolo, T. Bortolin, F. Petronilho, and F. Dal-Pizzol, “Oxidative stress and inflammatory markers in normal pregnancy and preeclampsia,” Journal of Obstetrics and Gynaecology Research, vol. 34, no. 6, pp. 948–951, 2008.
[26]  J. P. Granger, B. T. Alexander, M. T. Llinas, W. A. Bennett, and R. A. Khalil, “Pathophysiology of preeclampsia: linking placental ischemia/hypoxia with microvascular dysfunction,” Microcirculation, vol. 9, no. 3, pp. 147–160, 2002.
[27]  R. J. Levine and S. A. Karumanchi, “Circulating angiogenic factors in preeclampsia,” Clinical Obstetrics and Gynecology, vol. 48, no. 2, pp. 372–386, 2005.
[28]  S. Maynard, F. H. Epstein, and S. A. Karumanchi, “Preeclampsia and angiogenic imbalance,” Annual Review of Medicine, vol. 59, pp. 61–78, 2008.
[29]  A. Wang, S. Rana, and S. A. Karumanchi, “Preeclampsia: the role of angiogenic factors in its pathogenesis,” Physiology, vol. 24, no. 3, pp. 147–158, 2009.
[30]  R. L. Kendall and K. A. Thomas, “Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 22, pp. 10705–10709, 1993.
[31]  R. J. Levine, S. E. Maynard, C. Qian et al., “Circulating angiogenic factors and the risk of preeclampsia,” The New England Journal of Medicine, vol. 350, no. 7, pp. 672–683, 2004.
[32]  R. J. Levine, C. Lam, C. Qian et al., “Soluble endoglin and other circulating antiangiogenic factors in preeclampsia,” The New England Journal of Medicine, vol. 355, no. 10, pp. 992–1005, 2006.
[33]  S. E. Maynard, J. Y. Min, J. Merchan et al., “Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction hypertension, and proteinuria in preeclampsia,” Journal of Clinical Investigation, vol. 111, no. 5, pp. 649–658, 2003.
[34]  S. Venkatesha, M. Toporsian, C. Lam et al., “Soluble endoglin contributes to the pathogenesis of preeclampsia,” Nature Medicine, vol. 12, no. 6, pp. 642–649, 2006.
[35]  A. Makris, C. Thornton, J. Thompson et al., “Uteroplacental ischemia results in proteinuric hypertension and elevated sFLT-1,” Kidney International, vol. 71, no. 10, pp. 977–984, 2007.
[36]  F. Herse, A. C. Staff, L. Hering, D. N. Müller, F. C. Luft, and R. Dechend, “AT1-receptor autoantibodies and uteroplacental RAS in pregnancy and pre-eclampsia,” Journal of Molecular Medicine, vol. 86, no. 6, pp. 697–703, 2008.
[37]  Y. Xia, C. Z. Cissy, S. M. Ramin, and R. E. Kellems, “Angiotensin receptors, autoimmunity, and preeclampsia,” Journal of Immunology, vol. 179, no. 6, pp. 3391–3395, 2007.
[38]  Y. Xia and R. Kellems, “Receptor-activating autoantibodiesand disease: preeclampsia and bevond,” Expert Review of Clinical Immunology, vol. 7, no. 5, pp. 659–674, 2011.
[39]  G. Wallukat, V. Homuth, T. Fischer et al., “Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor,” Journal of Clinical Investigation, vol. 103, no. 7, pp. 945–952, 1999.
[40]  B. LaMarca, K. Wallace, and J. Granger, “Role of angiotensin II type I receptor agonistic autoantibodies (AT1-AA) in preeclampsia,” Current Opinion in Pharmacology, vol. 11, no. 2, pp. 175–179, 2011.
[41]  R. Dechend, C. Viedt, D. N. Müller et al., “AT1 receptor agonistic antibodies from preeclamptic patients stimulate NADPH oxidase,” Circulation, vol. 107, no. 12, pp. 1632–1639, 2003.
[42]  Y. Xia, H. Y. Wen, and R. E. Kellems, “Angiotensin II inhibits human trophoblast invasion through AT1 receptor activation,” The Journal of Biological Chemistry, vol. 277, no. 27, pp. 24601–24608, 2002.
[43]  Y. Xia, H. Wen, S. Bobst, M. C. Day, and R. E. Kellems, “Maternal autoantibodies from preeclamptic patients activate angiotensin receptors on human trophoblast cells,” Journal of the Society for Gynecologic Investigation, vol. 10, no. 2, pp. 82–93, 2003.
[44]  S. M. Bobst, M. C. Day, L. C. Gilstrap, Y. Xia, and R. E. Kellems, “Maternal autoantibodies from preeclamptic patients activate angiotensin receptors on human mesangial cells and induce interleukin-6 and plasminogen activator inhibitor-1 secretion,” American Journal of Hypertension, vol. 18, no. 3, pp. 330–336, 2005.
[45]  R. Dechend, V. Homuth, G. Wallukat et al., “AT1 receptor agonistic antibodies from preeclamptic patients cause vascular cells to express tissue factor,” Circulation, vol. 101, no. 20, pp. 2382–2387, 2000.
[46]  X. Yang, F. Wang, H. Chang et al., “Autoantibody against AT1 receptor from preeclamptic patients induces vasoconstriction through angiotensin receptor activation,” Journal of Hypertension, vol. 26, no. 8, pp. 1629–1635, 2008.
[47]  C. C. Zhou, Y. Zhang, R. A. Irani, et al., “Angiotensin receptor agonistic autoantibodies induce pre-eclampsia in pregnant mice,” Nature Medicine, vol. 14, pp. 855–862, 2008.
[48]  B. LaMarca, M. Parrish, L. F. Ray et al., “Hypertension in response to autoantibodies to the angiotensin II type i receptor (AT1-AA) in pregnant rats: role of endothelin-1,” Hypertension, vol. 54, no. 4, pp. 905–909, 2009.
[49]  B. LaMarca, G. Wallukat, M. Llinas, F. Herse, R. Dechend, and J. P. Granger, “Autoantibodies to the angiotensin type I receptor in response to placental ischemia and tumor necrosis factor α in pregnant rats,” Hypertension, vol. 52, no. 6, pp. 1168–1172, 2008.
[50]  J. P. Granger, B. B. LaMarca, K. Cockrell et al., “Reduced uterine perfusion pressure (RUPP) model for studying cardiovascular-renal dysfunction in response to placental ischemia,” Methods in Molecular Medicine, vol. 122, pp. 383–392, 2006.
[51]  B. B. LaMarca, W. A. Bennett, B. Alexander, et al., “Hypertension produced by reductions in uterine perfusion in the pregnant rat: role of tumor necrosis factor-α,” Hypertension, vol. 46, no. 4, pp. 1022–1025, 2005.
[52]  C. C. Zhou, S. Ahmad, T. Mi et al., “Autoantibody from women with preeclampsia induces soluble Fms-like tyrosine kinase-1 production via angiotensin type 1 receptor and calcineurin/nuclear factor of activated T-cells signaling,” Hypertension, vol. 51, no. 4, pp. 1010–1019, 2008.
[53]  C. C. Zhou, R. A. Irani, Y. Zhang et al., “Angiotensin receptor agonistic autoantibody-mediated tumor necrosis factor-α induction contributes to increased soluble endoglin production in preeclampsia,” Circulation, vol. 121, no. 3, pp. 436–444, 2010.
[54]  T. Walther, G. Wallukat, A. Jank et al., “Angiotensin II type 1 receptor agonistic antibodies reflect fundamental alterations in the uteroplacental vasculature,” Hypertension, vol. 46, no. 6, pp. 1275–1279, 2005.
[55]  A. H. Siddiqui, R. A. Irani, S. C. Blackwell, S. M. Ramin, R. E. Kellems, and Y. Xia, “Angiotensin receptor agonistic autoantibody is highly prevalent in preeclampsia: correlation with disease severity,” Hypertension, vol. 55, no. 2, pp. 386–393, 2010.
[56]  B. M. Sibai, “Diagnosis, prevention, and management of eclampsia,” Obstetrics and Gynecology, vol. 105, no. 2, pp. 402–410, 2005.
[57]  J. Hinchey, C. Chaves, B. Appignani et al., “A reversible posterior leukoencephalopathy syndrome,” The New England Journal of Medicine, vol. 334, no. 8, pp. 494–500, 1996.
[58]  J. Tollemar, O. Ringden, B. G. Ericzon, et al., “Cyclosporine-associated central nervous system toxicity,” The New England Journal of Medicine, vol. 318, no. 12, pp. 788–789, 1988.
[59]  J. P. Sloane, K. Y. Lwin, M. E. Gore, et al., “Disturbannce of blood-brain barrier after bone-marrow transplantation,” The Lancet, vol. 2, no. 8449, pp. 280–281, 1985.
[60]  M. Verbeke, J. van de Voorde, L. de Ridder, and N. Lameire, “Functional analysis of vascular dysfunction in cyclosporin treated rats,” Cardiovascular Research, vol. 28, no. 8, pp. 1152–1156, 1994.
[61]  V. H. Lee, E. F. M. Wijdicks, E. M. Manno, and A. A. Rabinstein, “Clinical spectrum of reversible posterior leukoencephalopathy syndrome,” Archives of Neurology, vol. 65, no. 2, pp. 205–210, 2008.
[62]  W. S. Bartynski, “Posterior reversible encephalopathy syndrome, part 1: fundamental imaging and clinical features,” American Journal of Neuroradiology, vol. 29, no. 6, pp. 1036–1042, 2008.
[63]  W. S. Bartynski and J. F. Boardman, “Distinct imaging patterns and lesion distribution in posterior reversible encephalopathy syndrome,” American Journal of Neuroradiology, vol. 28, no. 7, pp. 1320–1327, 2007.
[64]  E. Oehm, M. Reinhard, C. Keck, T. Els, J. Spreer, and A. Hetzel, “Impaired dynamic cerebral autoregulation in eclampsia,” Ultrasound in Obstetrics and Gynecology, vol. 22, no. 4, pp. 395–398, 2003.
[65]  E. Oehm, A. Hetzel, T. Els et al., “Cerebral hemodynamics and autoregulation in reversible posterior leukoencephalopathy syndrome caused by pre-/eclampsia,” Cerebrovascular Diseases, vol. 22, no. 2-3, pp. 204–208, 2006.
[66]  M. A. Belfort, M. W. Varner, D. S. Dizon-Townson, C. Grunewald, and H. Nisell, “Cerebral perfusion pressure, and not cerebral blood flow, may be the critical determinant of intracranial injury in preeclampsia: a new hypothesis,” American Journal of Obstetrics and Gynecology, vol. 187, no. 3, pp. 626–634, 2002.
[67]  M. J. Cipolla, “Cerebrovascular function in pregnancy and eclampsia,” Hypertension, vol. 50, no. 1, pp. 14–24, 2007.
[68]  F. Mattar and B. M. Sabai, “Eclampsia. VIII. Risk factors for maternal mortality,” American Journal of Obstetrics and Gynecology, vol. 182, no. 2, pp. 307–312, 2000.
[69]  B. M. Sibai, “Eclampsia. VI. Maternal-perinatal outcome in 254 ocnsecutive cases,” American Journal of Obstetrics and Gynecology, vol. 163, no. 3, pp. 1049–1055, 1990.
[70]  O. Amburgey, A. C. Chapman, V. May, I. M. Bernstein, and M. J. Cipolla, “Plasma from preeclamptic women increases blood-brain barrier permeability: role of vascular endothelial growth factor signaling,” Hypertension, vol. 56, no. 5, pp. 1003–1008, 2010.
[71]  N. Pelisch, N. Hosomi, M. Ueno et al., “Blockade of AT1 receptors protects the blood-brain barrier and improves cognition in dahl salt-sensitive hypertensive rats,” American Journal of Hypertension, vol. 24, no. 3, pp. 362–368, 2011.
[72]  B. M. Sibai, “Diagnosis and management of gestational hypertension and preeclampsia,” Obstetrics and Gynecology, vol. 102, no. 1, pp. 181–192, 2003.
[73]  D. Altman, G. Carroli, L. Duley et al., “Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie trial: a randomised placebo-controlled trial,” The Lancet, vol. 359, no. 9321, pp. 1877–1890, 2002.
[74]  M. Belfort, J. Allred, and G. Dildy, “Magnesium sulfate decreases cerebral perfusion pressure in preeclampsia,” Hypertension in Pregnancy, vol. 27, no. 4, pp. 315–327, 2008.
[75]  B. T. Alexander, K. Cockrell, F. D. Cline, M. T. Llinas, M. Sedeek, and J. P. Granger, “Effect of angiotensin II synthesis blockade on the hypertensive response to chronic reductions in uterine perfusion pressure in pregnant rats,” Hypertension, vol. 38, no. 3, pp. 742–745, 2001.
[76]  N. Roger, I. Popovic, P. Madelenat, and D. Mahieu-Caputo, “Fetal toxicity of angiotensin-II-receptor inhibitors. Case report,” Gynecologie Obstetrique Fertilite, vol. 35, no. 6, pp. 556–560, 2007.
[77]  M. A. Bos-Thompson, D. Hillarire-Buys, F. Muller, et al., “Fetal toxic effects of angiotensin II receptor antagonists: case report and follow-up after birth,” The Annals of Pharmacotherapy, vol. 39, no. 1, pp. 157–161, 2005.
[78]  K. Kato, M. Okuda, H. Ishikawa, T. Takahashi, and F. Hirahara, “Oligohydramnios and pulmonary hypoplasia: a case in which involvement of an angiotensin II receptor antagonist was suspected,” Journal of Obstetrics and Gynaecology Research, vol. 34, no. 2, pp. 242–246, 2008.
[79]  C. A. Hubel, G. Wallukat, M. Wolf et al., “Agonistic angiotensin II type 1 receptor autoantibodies in postpartum women with a history of preeclampsia,” Hypertension, vol. 49, no. 3, pp. 612–617, 2007.
[80]  M. C. Chames, J. C. Livingston, T. S. Invster, et al., “Late postpartum eclampsia: a preventable disease?” American Journal of Obstetrics and Gynecology, vol. 186, no. 6, pp. 1174–1177, 2002.


comments powered by Disqus