Journal ArticleDOI
Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia
Keizo Kanasaki,Kristin Palmsten,Hikaru Sugimoto,Shakil Ahmad,Yuki Hamano,Liang Xie,Samuel Parry,Hellmut G. Augustin,Vincent H. Gattone,Judah Folkman,Jerome F. Strauss,Raghu Kalluri,Raghu Kalluri,Raghu Kalluri +13 more
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TLDR
The studies identify a genetic mouse model for pre-eclampsia and suggest that 2-ME may have utility as a plasma and urine diagnostic marker for this disease, and may also serve as a therapeutic supplement to prevent or treat this disorder.Abstract:
Despite intense investigation, mechanisms that facilitate the emergence of the pre-eclampsia phenotype in women are still unknown. Placental hypoxia, hypertension, proteinuria and oedema are the principal clinical features of this disease. It is speculated that hypoxia-driven disruption of the angiogenic balance involving vascular endothelial growth factor (VEGF)/placenta-derived growth factor (PLGF) and soluble Fms-like tyrosine kinase-1 (sFLT-1, the soluble form of VEGF receptor 1) might contribute to some of the maternal symptoms of pre-eclampsia. However, pre-eclampsia does not develop in all women with high sFLT-1 or low PLGF levels, and it also occurs in some women with low sFLT-1 and high PLGF levels. Moreover, recent experiments strongly suggest that several soluble factors affecting the vasculature are probably elevated because of placental hypoxia in the pre-eclamptic women, indicating that upstream molecular defect(s) may contribute to pre-eclampsia. Here we show that pregnant mice deficient in catechol-O-methyltransferase (COMT) show a pre-eclampsia-like phenotype resulting from an absence of 2-methoxyoestradiol (2-ME), a natural metabolite of oestradiol that is elevated during the third trimester of normal human pregnancy. 2-ME ameliorates all pre-eclampsia-like features without toxicity in the Comt(-/-) pregnant mice and suppresses placental hypoxia, hypoxia-inducible factor-1alpha expression and sFLT-1 elevation. The levels of COMT and 2-ME are significantly lower in women with severe pre-eclampsia. Our studies identify a genetic mouse model for pre-eclampsia and suggest that 2-ME may have utility as a plasma and urine diagnostic marker for this disease, and may also serve as a therapeutic supplement to prevent or treat this disorder.read more
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Journal ArticleDOI
Preeclampsia, a Disease of the Maternal Endothelium The Role of Antiangiogenic Factors and Implications for Later Cardiovascular Disease
TL;DR: Preeclampsia is a systemic vascular disorder that may also affect the liver and the brain in the mothers and is named not only for the liver involvement, but also for the disorder of the coagulation system that develops.
Journal ArticleDOI
Preeclampsia: Pathophysiology, Challenges, and Perspectives
Sarosh Rana,Elizabeth R. Lemoine,Elizabeth R. Lemoine,Joey P. Granger,S. Ananth Karumanchi,S. Ananth Karumanchi +5 more
TL;DR: The current evidence for the role of abnormal placentation and therole of placental factors such as the antiangiogenic factor, sFLT1 (soluble fms-like tyrosine kinase 1) in the pathogenesis of the maternal syndrome of preeclampsia is discussed.
Journal ArticleDOI
Inflammation and Pregnancy
John R. G. Challis,Charles J. Lockwood,Leslie Myatt,Jane E. Norman,Jerome F. Strauss,Felice Petraglia +5 more
TL;DR: In this article, the balance of Th1 (cell mediated immunity) and Th2 (humoral immunity) cytokines is characterized by an initial prevalence of Th2 cytokines, followed by a progressive shift toward Th1 predominance late in gestation, that when is abnormal, may initiate and intensify the cascade of inflammatory cytokine production involved in adverse pregnancy outcomes.
Journal ArticleDOI
Pre-eclampsia part 1: current understanding of its pathophysiology
TL;DR: The diagnosis, classification, clinical manifestations and putative pathogenetic mechanisms of pre-eclampsia are discussed.
Journal ArticleDOI
Pathogenesis of Preeclampsia
TL;DR: The recent discoveries of upregulated antiangiogenic factors provide promise for future testing to predict and diagnose preeclampsia as well as therapeutic targets for amelioration of the clinical disease.
References
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Journal ArticleDOI
Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia
Sharon Maynard,Jiang Yong Min,Jaime R. Merchan,Kee-Hak Lim,Jianyi Li,Susanta Mondal,Towia A. Libermann,James P. Morgan,Frank W. Sellke,Isaac E. Stillman,Franklin H. Epstein,Vikas P. Sukhatme,S. Ananth Karumanchi +12 more
TL;DR: It is confirmed that placental soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of VEGF and placental growth factor (PlGF), is upregulated in preeclampsia, leading to increased systemic levels of sFlt 1 that fall after delivery, and observations suggest that excess circulating sFelt1 contributes to the pathogenesis of preeClampsia.
Journal ArticleDOI
Circulating Angiogenic Factors and the Risk of Preeclampsia
Richard J. Levine,Sharon Maynard,Cong Qian,Kee-Hak Lim,Lucinda England,Kai F. Yu,Enrique F. Schisterman,Ravi Thadhani,Benjamin P. Sachs,Franklin H. Epstein,Bahaeddine M Sibai,Vikas P. Sukhatme,S. Ananth Karumanchi +12 more
TL;DR: Alterations in the levels of sFlt-1 and free PlGF were greater in women with an earlier onset of preeclampsia and in women in whom preeClampsia was associated with a small-for-gestational-age infant.
Journal ArticleDOI
Latest advances in understanding preeclampsia.
TL;DR: Recent work on the causes of preeclampsia is summarized, which reveals a new mode of maternal immune recognition of the fetus, relevant to the condition, and circulating factors derived from the placenta are now better understood.
Journal ArticleDOI
Hypoxia-inducible factor 1: master regulator of O2 homeostasis
TL;DR: Hypoxia-inducible factor 1 is a transcription factor that mediates essential homeostatic responses to reduced O2 availability in mammals and the effects of HIF-1 deficiency on cellular physiology and embryonic development are provided.
Journal ArticleDOI
Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior
Joseph A. Gogos,Maria A. Morgan,Victoria N. Luine,Miklós Sántha,Sonoko Ogawa,Donald W. Pfaff,Maria Karayiorgou +6 more
TL;DR: The results provide conclusive evidence for an important sex- and region-specific contribution of COMT in the maintenance of steady-state levels of catecholamines in the brain and suggest a role for comT in some aspects of emotional and social behavior in mice.
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