[en] Preeclampsia (PE) is a pregnancy-specific syndrome characterized by hypertension, proteinuria and edema, which resolves on placental delivery. It is thought to be the consequence of impaired placentation due to inadequate trophoblastic invasion of the maternal spiral arteries. In PE the maternal plasma concentration of free vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) is decreased whereas the concentration of soluble fms-like tyrosine kinase-1 (sFlt-1) and of soluble endoglin (sEng) is increased. These soluble receptors may bind VEGF, PLGF and TGFβ1 and TGFβ3 in the maternal circulation, causing endothelial dysfunction in many maternal tissues. Hence there is a view that the pathogenesis is more or less clarified. According to the vascular theory, poor placentation leads to poor uteroplacental perfusion and hypoxia, which stimulates sFlt-1 and sEng production causing the maternal syndrome. This assumption has been recently challenged. The role of hypoxia as the main stimulus for release of sFlt-1 has been questioned and the role of inflammatory mechanisms has been emphasized. According to this inflammatory theory, poor placentation may predispose more to placental oxidative stress than hypoxia and endothelial dysfunction may be part of a broader disorder of systemic inflammation. Finally, the recent demonstration of activating auto-antibodies to the angiotensin 1 receptor that experimentally play a major pathogenic role in PE further suggests a pleiotropism of aetiologies for this condition. The purpose of this review is to critically evaluate the recent hypotheses and their possible insights on early diagnosis, prevention and treatment.
Disciplines :
Reproductive medicine (gynecology, andrology, obstetrics)
Author, co-author :
Foidart, Jean-Michel ; Université de Liège - ULiège > Département des sciences cliniques > Gynécologie - Obstétrique - Labo de biologie des tumeurs et du développement
Schaaps, Jean-Pierre ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Embryologie
AbdAlla S., Lother H., el Massiery A., and Quitterer U. Increased AT(1) receptor heterodimers in PE mediate enhanced angiotensin II responsiveness. Nat. Med. 7 (2001) 1003-1009
Ahmad S., and Ahmed A. Elevated placental soluble vascular endothelial growth factor receptor-1 inhibits angiogenesis in PE. Circ. Res. 95 (2004) 884-891
Baumwell S., and Karumanchi S.A. PE: clinical manifestations and molecular mechanisms. Nephron. Clin. Pract. 106 2 (2007) c72-c81
Blouin C.C., Pagé E.L., Soucy G.M., and Richard D.E. Hypoxic gene activation by lipopolysaccharide in macrophages: implication of hypoxia-inducible factor 1alpha. Blood 103 (2004) 1124-1130
Davidge S.T. Oxidative stress and altered endothelial cell function in PE. Semin. Reprod. Endocrinol. 16 (1998) 65-73
De Wolf F., De Wolf-Peeters C., Brosens I., and Robertson W.B. The human placental bed: electron microscopic study of trophoblastic invasion of spiral arteries. Am. J. Obstet. Gynecol. 137 (1980) 58-70
Eremina V., Sood M., Haigh J., Nagy A., Lajoie G., Ferrara N., Gerber H.P., Kikkawa Y., Miner J.H., and Quaggin S.E. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J. Clin. Invest. 111 (2003) 707-716
Foidart J.M., Hustin J., Dubois M., and Schaaps J.P. The human placenta becomes haemochorial at the 13th week of pregnancy. Int. J. Dev. Biol. 36 (1992) 451-453
Founds S.A., Conley Y.P., Lyons-Weiler J.F., Jeyabalan A., Allen Hogge W., and Conrad K.P. Altered global gene expression in first trimester placentas of women destined to develop preeclampsia. Placenta (2008) November 20 (Epub ahead of print)
Görlach A., and Bonello S. The cross-talk between NF-kB and HIF-1: further evidence for a significant liaison. Biochem. J. 412 (2008) e17-e19
Hubel C.A., McLaughlin M.K., Evans R.W., Hauth B.A., Sims C.J., and Roberts J.M. Fasting serum triglycerides, free fatty acids, and malondialdehyde are increased in PE, are positively correlated, and decrease within 48 hours post partum. Am. J. Obstet. Gynecol. 174 (1996) 975-982
Hung T.H., and Burton G.J. Hypoxia and reoxygenation: a possible mechanism for placental oxidative stress in PE. Taiwan J. Obstet. Gynecol. 45 (2006) 189-200
Hustin J., and Schaaps J.P. Echo(cardio)graphic and anatomic studies of the materno trophoblastic border during the first trimester of pregnancy. Am. J. Obstet. Gynecol. 157 1 (1987) 162-168
Kolben M., Lopens A., Blaser J., Huber A., Frank M., Wilhelm O., Wilhelm S., Schneider K.T., Ulm K., Tschesche H., et al. Measuring the concentration of various plasma and placenta extract proteolytic and vascular factors in pregnant patients with HELLP syndrome, pre-/eclampsia and highly pathologic Doppler flow values. Gynaekol. Geburtsh. Rundsch. 35 Suppl. 1 (1995) 126-131
Kontic-Vucinic O., Terzic M., and Radunovic N. The role of antioxidant vitamins in hypertensive disorders of pregnancy. J. Perinat. Med. 36 4 (2008) 282-290
Kuenen B.C., Levi M., Meijers J.C., Kakkar A.K., van Hinsbergh V.W., Kostense P.J., Pinedo H.M., and Hoekman K. Analysis of coagulation cascade and endothelial cell activation during inhibition of vascular endothelial growth factor/vascular endothelial growth factor receptor pathway in cancer patients. Arterioscler. Thromb. Vasc. Biol. 22 (2002) 1500-1505
Karumanchi S.A., and Lindheimer M.D. Advances in the understanding of eclampsia. Curr. Hypertens. Rep. 10 August (4) (2008) 305-312
Levine R.J., Lam C., Qian C., Yu K.F., Maynard S.E., Sachs B.P., Sibai B.M., Epstein F.H., Romero R., Thadhani R., and Karumanchi S.A. Soluble endoglin and other circulating antiangiogenic factors in PE. N. Engl. J. Med. 355 (2006) 992-1005
Li X., Shams M., Zhu J., Khalig A., Wilkes M., Whittle M., Barnes N., and Ahmed A. 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. 101 (1998) 442-454
Munaut C., Lorquet S., Pequeux C., Blacher S., Berndt S., Frankenne F., and Foidart J.M. Hypoxia is responsible for soluble vascular endothelial growth factor receptor-1 (VEGFR-1) but not for soluble endoglin induction in villous trophoblast. Hum. Reprod. 23 June (6) (2008) 1407-1415
Maynard S., Epstein F.H., and Karumanchi S.A. PE and angiogenic imbalance. Annu. Rev. Med. 59 (2008) 61-78
Maynard S.E., Min J.Y., Merchan J., Lim K.H., Li J., Mondal S., Libermann T.A., Morgan J.P., Sellke F.W., Stillman I.E., Epstein F.H., Sukhatme V.P., and Karumanchi S.A. Excess placental soluble fms-like tyrosine kinase 1 (sFlt-1) may contribute to endothelial dysfunction, hypertension, and proteinuria in PE. J. Clin. Invest. 111 (2003) 649-658
Myatt L., Rosenfield R.B., Eis A.L., Brockman D.E., Greer I., and Lyall F. Nitrotyrosine residues in placenta. Evidence of peroxynitrite formation and action. Hypertension 28 (1996) 488-493
Nevo O., Soleymanlou N., Wu Y., Xu J., Kingdom J., Many A., 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. 291 (2006) R1085-R1093
Pregnancy: Report of the National High Blood Pressure Education Program Working Group on high blood pressure in pregnancy. Am. J. Obstet. Gynecol. 183 (2000) S1-S22
Qin Z. Newly developed angiotensin II-infused experimental models in vascular biology. Regul. Pept. 150 (2008) 1-6
Redman C., and Sargent I.L. Placental stress and PE: a revised view placenta 30, supplement A. Trophoblast Res. 23 (2009) S38-S42
Redman C.W., and Sargent I.L. Latest advances in understanding PE. Science 308 (2005) 1592-1594
Redman C.W.G., and Sargent I.L. Circulating microparticles in normal pregnancy and PE placenta 29, supplement A. Trophoblast Res. 22 (2008) S73-S77
Rius J., Guma M., Schachtrup C., Akassoglou K., Zinkernagel A.S., Nizet V., et al. NF-kB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature 453 (2008) 807-811
Robertson W.B., Brosens I., and Dixon H.G. The pathological response of the vessels of the placental bed to hypertensive pregnancy. J. Pathol. Bacteriol. 93 (1967) 581-592
Rumbold A., Duley L., Crowther C.A., and Haslam R.R. Antioxidants for preventing PE. Cochrane Database Syst. Rev. January (1) (2008) CD004227
Schaaps J.P., Tsatsaris V., Goffin F., Brichant J.F., Delbecque K., Tebache M., Collignon L., Retz M.C., and Foidart J.M. Shunting the intervillous space: new concepts in human uteroplacental vascularization. Am. J. Obstet. Gynecol. 192 January (1) (2005) 323-332
Shah D.M. Preeclampsia, new insights. Curr. Opin. Nephrol. Hypertens. 16 (2007) 213-220
Stella C.L., and Sibai B.M. Preeclampsia: diagnosis and management of the atypical presentation. J. Matern. Fetal Neonatal Med. 19 (2006) 381-386
Taylor C.T. Interdependent roles for hypoxia inducible factor and nuclear factor-kB in hypoxic inflammation. J. Physiol. 586 (2008) 4055-4059
van Uden P., Kenneth N.S., and Rocha S. Regulation of hypoxia-inducible factor-1alpha by NF-kB. Biochem. J. 412 (2008) 477-484
Venkatesha S., Toporsian M., Lam C., Hanai J., Mammoto T., Kim Y.M., Bdolah Y., Lim K.H., Yuan H.T., Libermann T.A., Stillman I.E., Roberts D., D'Amore P.A., Epstein F.H., Sellke F.W., Romero R., Sukhatme V.P., Letarte M., and Karumanchi S.A. Soluble endoglin contributes to the pathogenesis of PE. Nat. Med. 12 (2006) 642-649
Wallukat G., Homuth V., Fischer T., Lindschau C., Horstkamp B., Jupner A., Baur E., Nissen E., Vetter K., Neichel D., Dudenhausen J.W., Haller H., and Luft F.C. Patients with PE develop agonistic autoantibodies against the angiotensin AT1 receptor. J. Clin. Invest. 103 (1999) 945-952
Xia Y., Ramin S.M., and Kellems R.E. Potential roles of angiotensin receptor-activating autoantibody in the pathophysiology of PE. Hypertension 50 August (2) (2007) 269-275
Yang J.C., Haworth L., Sherry R.M., Hwu P., Schwartzentruber D.J., Topalian S.L., Steinberg S.M., Chen H.X., and Rosenberg S.A. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N. Engl. J. Med. 349 (2003) 427-434
Zhou Y., Damsky C.H., and Fisher S.J. PE is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. One cause of defective endovascular invasion in this syndrome?. J. Clin. Invest. 99 (1997) 2152-2164