Angiogene Faktoren und ihre Rolle in der Entstehung und Vorhersage der Präeklampsie

Zusammenfassung

Obwohl die Ätiologie der Präeklampsie noch immer nicht vollständig geklärt werden konnte, gibt es mittlerweile überzeugende Hinweise dafür, dass eine Dysbalance zwischen angiogenen Faktoren wie placental growth factor (PlGF) und anti-angiogenen Faktoren wie soluble fms-like tyrosine kinase 1 (sFlt1) und soluble Endoglin (sENG) ein zentrales pathogenetisches Ereignis bei der Entstehung der Präeklampsie ist. Durch die Erforschung angiogener Faktoren scheint man, wenn nicht der Ursache der Präeklampsie, so doch den entscheidenden pathogenetischen Mediatoren sehr nahe gekommen zu sein. Da antiangiogene Faktoren wie sFlt1 und sENG bereits Wochen vor Manifestation einer Präeklampsie sehr stark erhöht im mütterlichen Blut messbar sind und maternale Serumkonzentrationen dieser Faktoren gut mit dem klinischen Verlauf korrelieren, ist jetzt im Risikokollektiv eine sehr gute klinische Prognose möglich. Im Risikokollektiv von Schwangeren mit uteriner Perfusionsstörung im 2. Trimenon hat der Doppler allein nur eine Spezifität von 60% bzw. eine positive Vorhersage von 58% bezüglich aller später auftretender Komplikationen (PE+IUGR). Die parallele Messung von sFlt1 und PlGF kann die Erkennung einer early-onset-Präeklampsie (<34. SSW) auf 83% Sensitivität, 95% Spezifität und 71% positive Vorhersage deutlich verbessern. Bei kombinierter Messung von uterinem Doppler, sENG und sFlt1 betrug die Sensitivität hinsichtlich early-onset-Präeklampsie sogar 99% und die Spezifität 93%. Der nächste Schritt wird die Entwicklung einer theoretisch möglichen therapeutischen Intervention sein, die durch die Beeinflussung des angiogenen-anti-angiogenen Gleichgewichts die präeklamptischen Symptome positiv beeinflussen kann.

Abstract

Angiogenic factors like placental growth factor (PlGF) and its anti-angiogenic antagonists soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng) are closely related to the pathogenesis of preeclampsia and intrauterine growth restriction (IUGR). The discovery and investigation of these angiogenic factors could characterize important pathogenetic mediators of preeclampsia or even the cause for placental dysfunctions. These anti-angiogenic proteins are dramatically elevated in maternal circulation weeks prior to the onset of the syndrome preeclampsia. Since it is known that altered maternal sFlt1, sEng and PlGF levels are detectable weeks prior to the onset of these pregnancy complications, it was the aim of the study to investigate the predictive value of these markers in high-risk second trimester pregnancies characterized by abnormal uterine perfusion. Using both factors, sFlt1 and PlGF, early-onset preeclampsia can be predicted with 83% sensitivity and 95% specificity. Combined analysis of sEng and sFlt1 is able to predict early-onset PE even with a sensitivity of 100% and a specificity of 93.3%. This shows, that the concurrent measurement of uterine perfusion and angiogenic factors allows an efficient prediction of early-onset pregnancy complications, particularly preeclampsia. The next step will be the development of therapeutic tools that have positive impact on the clinical symptoms via the inhibition of sFlt1 and or sEng.

Präeklampsie - angiogene Fraktoren - Prädiktion - PLGF - sFlt 1 - sEng

preeclampsia - angiogenic factors - predictive value - PlGF - sFlt 1 - sEng

Literatur

• 1 Sibai B, Dekker G, Kupferminc M. Pre-eclampsia.  Lancet. 2005;  365 785-799
• 2 Roberts JM, Pearson GD, Cutler JA. et al . Summary of the NHLBI Working Group on Research on Hypertension During Pregnancy.  Hypertens Pregnancy. 2003;  22 109-127
• 3 Conde-Agudelo A, Villar J, Lindheimer M. World Health Organization systematic review of screening tests for preeclampsia.  Obstet Gynecol. 2004;  104 ((6)) 1367-1391
• 4 Chien PF, Arnott N, Gordon A. et al . How useful is uterine artery Doppler flow velocimetry in the prediction of pre-eclampsia, intrauterine growth retardation and perinatal death? An overview.  Brit J Obstet Gynaecol. 2000;  107 196-208
• 5 Martin AM, Bindra R, Curcio P. et al . Screening for pre-eclampsia and fetal growth restriction by uterine artery Doppler at 11–14 weeks of gestation.  Ultrasound Obstet Gynecol. 2001;  18 583-586
• 6 Benedetto C, Valensise H, Marozio L. et al . A two-stage screening test for pregnancy-induced hypertension and preeclampsia.  Obstet Gynecol. 1998;  92 1005-1011
• 7 Lam C, Lim KH, Karumanchi SA. Circulating angiogenic factors in the pathogenesis and prediction of preeclampsia.  Hypertension. 2005;  46 1077-1085
• 8 Levine RJ, Karumanchi SA. Circulating angiogenic factors in preeclampsia.  Clin Obstet Gynecol. 2005;  48 372-386
• 9 Tjoa ML, Levine RJ, Karumanchi SA. Angiogenic factors and preeclampsia.  Front Biosci. 2007;  12 2395-2402
• 10 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;  111 649-658
• 11 Venkatesha S, Toporsian M, Lam C. et al . Soluble endoglin contributes to the pathogenesis of preeclampsia.  Nat Med. 2006;  12 642-649
• 12 Levine RJ, Maynard SE, Qian C. et al . Circulating angiogenic factors and the risk of preeclampsia.  N Engl J Med. 2004;  350 672-683
• 13 Hertig A, Berkane N, Lefevre G. et al . Maternal serum sFlt1 concentration is an early and reliable predictive marker of preeclampsia.  Clin Chem. 2004;  50 1702-1703
• 14 Taylor RN, Grimwood J, Taylor RS. et al . Longitudinal serum concentrations of placental growth factor: evidence for abnormal placental angiogenesis in pathological pregnancies.  Am J Obstet Gynecol. 2003;  188 177-182
• 15 Tidwell SC, Ho HN, Chiu WH. et al . Low maternal serum levels of placental growth factor as an antecedent of clinical preeclampsia.  Am J Obstet Gynecol. 2001;  184 1267-1272
• 16 Thadhani R, Mutter WP, Wolf M. et al . First trimester placental growth factor and soluble fms-like tyrosine kinase 1 and risk for preeclampsia.  J Clin Endocrinol Metab. 2004;  89 770-775
• 17 Tsatsaris V, Goffin F, Munaut C. et al . Overexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients: pathophysiological consequences.  J Clin Endocrinol Metab. 2003;  88 5555-5563
• 18 Stepan H, Geide A, Faber R. Soluble fms-like tyrosine kinase 1.  N Engl J Med. 2004;  351 2241-2242
• 19 Stepan H, Unversucht A, Wessel N. et al . Predictive value of maternal angiogenic factors in second trimester pregnancies with abnormal uterine perfusion.  Hypertension. 2007;  49 818-824
• 20 Crispi F, Dominquez C, Llurba E. et al . Placental angiogenic growth factors and uterine artery Doppler findings for characterization of different subsets in preeclampsia and in isolated intrauterine growth restriction.  Am J Obstet Gynecol. 2006;  195 201-207
• 21 Romero R, Nien JK, Espinoza J. et al . A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate.  J Matern Fetal Neonatal Med. 2008;  21 9-23
• 22 Levine RJ, Lam C, Qian C. et al . Soluble endoglin and other circulating antiangiogenic factors in preeclampsia.  N Engl J Med. 2006;  355 992-1005
• 23 Stepan H, Krämer T, Faber R. Maternal plasma concentrations of soluble endoglin in pregnancies with intrauterine growth restriction.  J Clin Endocrinol Metabol. 2007;  92 2831-2834
• 24 Stepan H, Geipel A, Schwarz F. et al . Circulatory soluble endoglin and its predictive value for preeclampsia in second-trimester pregnancies with abnormal uterine perfusion.  Am J Obstet Gynecol. 2008;  198 175 e171-176
• 25 Nagamatsu T, Fujii T, Kusumi M. et al . Cytotrophoblasts up-regulate soluble fms-like tyrosine kinase-1 expression under reduced oxygen: an implication for the placental vascular development and the pathophysiology of preeclampsia.  Endocrinology. 2004;  145 ((11)) 4838-4845
• 26 Karumanchi SA, Bdolah Y. Hypoxia and sFlt-1 in preeclampsia: the “chicken-and-egg” question.  Endocrinology. 2004;  145 ((11)) 4835-4837
• 27 Bdolah Y, Lam C, Rajakumar A. et al . Twin pregnancy and the risk of preeclampsia: bigger placenta or relative ischemia?.  Am J Obstet Gynecol. 2008;  198 ((4)) 428 , e1–6
• 28 Rana S, Venkatesha S, DePaepe M. et al . Cytomegalovirus-induced mirror syndrome associated with elevated levels of angiogenic factors.  Obstet Gynecol. 2007;  109 549-552
• 29 Stepan H, Faber R. Cytomegalovirus-induced mirror syndrome associated with elevated levels of angiogenic factors.  Obstet Gynecol. 2007;  109 1205-1206
• 30 Espinoza J, Romero R, Nien JK. et al . A role of the anti-angiogenic factor sVEGFR-1 in the ‘mirror syndrome’ (Ballantyne's syndrome).  J Matern Fetal Neonatal Med. 2006;  19 ((10)) 607-613
• 31 Stepan H, Faber R. Elevated sFlt1 level and preeclampsia with parvovirus-induced hydrops.  N Engl J Med. 2006;  354 1857-1858

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