Soluble endoglin contributes to the pathogenesis of preeclampsia

Venkatesha, Shivalingappa; Toporsian, Mourad; Lam, Chun; Hanai, Jun‐ichi; Mammoto, Tadanori; Kim, Yeon M.; Bdolah, Yuval; Lim, Kee-Hak; Yuan, Hai-Tao; Libermann, Towia A.; Stillman, Isaac E.; Roberts, Drucilla J.; D'Amore, Patricia A.; Epstein, Franklin H.; Sellke, Frank W.; Romero, Roberto; Sukhatme, Vikas P.; Letarte, Michelle; Karumanchi, S. Ananth

doi:10.1038/nm1429

Cited by 1,642 publications

(1,581 citation statements)

References 48 publications

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“…It is well accepted that the majority of pregnant women who subsequently develop hypertension in pregnancy exhibit abnormalities in maternal hemodynamics before the clinical development of hypertension, with or without aberrations in circulating angiogenic proteins that regulate vascular function early in pregnancy 3, 4, 5. The clinical syndromes of hypertension in pregnancy are distinctly heterogeneous.…”

Section: Introductionmentioning

confidence: 99%

Phenotypes of Pregnant Women Who Subsequently Develop Hypertension in Pregnancy

McLaughlin

Zhang

Lye

et al. 2018

JAHA

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BackgroundHypertensive disorders complicating pregnancy are a major cause of maternal death. Our objective was to evaluate maternal clinical, hemodynamic, and placental prognostic indicators in a consolidated manner to identify women who develop hypertension in pregnancy.Methods and ResultsTwenty‐six normotensive pregnant women from a specialized Placenta Clinic at increased risk of developing de novo hypertension and 20 normotensive healthy pregnant controls were recruited at 22 to 26 weeks' gestation. Fourteen maternal clinical, hemodynamic, and placental characteristics were assessed in the second trimester and aggregated. Principal component analysis of this combined data set determined that 3 dimensions accounted for 56% of the cohort variability. The first dimension accounted for 31% of the cohort variability, with significant contributions from total peripheral resistance, endoglin, and cardiac output. The second dimension was predominantly influenced by body mass index and mean arterial pressure, while uric acid and myeloperoxidase mainly contributed to the third dimension. Unsupervised clustering identified 3 groups within this combined data set. Total peripheral resistance was the most significant distinguishing parameter between these groups (P<0.0001), followed by placental growth factor, endoglin, and cardiac output (P<0.0001). Using these 4 parameters, a receiver operating curve was constructed with an area under the curve of 0.975 (95% confidence interval 0.93–1) for the prediction of developing hypertension in pregnancy.ConclusionsConsolidated assessment of prognostic indicators in the second trimester of pregnancy may be useful to characterize and distinguish pathways by which women may develop hypertension in pregnancy. This approach could contribute to the development of pathway‐specific preventative and antihypertensive treatment strategies.

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Section: Introductionmentioning

confidence: 99%

Phenotypes of Pregnant Women Who Subsequently Develop Hypertension in Pregnancy

McLaughlin

Zhang

Lye

et al. 2018

JAHA

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“…Endoglin is not directly involved in TGF‐β receptor signaling but modulates signaling responses of multiple members of the TGF‐β family 13. Mutation or abnormal expression of endoglin is the etiological reason for hereditary hemorrhagic telangiectasia or preeclampsia, respectively, which are closely related to malformation and dysfunction of blood vessels 14, 15. Inhibiting endoglin by gene knockdown in ECs inhibits TGF‐β/ALK1 signaling, and potentiates TGF‐β/ALK5 signaling,16, 17, 18 resulting in reduced proliferation 17, 19.…”

Section: Introductionmentioning

confidence: 99%

miR‐342‐5p Is a Notch Downstream Molecule and Regulates Multiple Angiogenic Pathways Including Notch, Vascular Endothelial Growth Factor and Transforming Growth Factor β Signaling

Yan

Cao

Liang

et al. 2016

JAHA

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BackgroundEndothelial cells (ECs) form blood vessels through angiogenesis that is regulated by coordination of vascular endothelial growth factor (VEGF), Notch, transforming growth factor β, and other signals, but the detailed molecular mechanisms remain unclear.Methods and ResultsSmall RNA sequencing initially identified miR‐342‐5p as a novel downstream molecule of Notch signaling in ECs. Reporter assay, quantitative reverse transcription polymerase chain reaction and Western blot analysis indicated that miR‐342‐5p targeted endoglin and modulated transforming growth factor β signaling by repressing SMAD1/5 phosphorylation in ECs. Transfection of miR‐342‐5p inhibited EC proliferation and lumen formation and reduced angiogenesis in vitro and in vivo, as assayed by using a fibrin beads–based sprouting assay, mouse aortic ring culture, and intravitreal injection of miR‐342‐5p agomir in P3 pups. Moreover, miR‐342‐5p promoted the migration of ECs, accompanied by reduced endothelial markers and increased mesenchymal markers, indicative of increased endothelial–mesenchymal transition. Transfection of endoglin at least partially reversed endothelial–mesenchymal transition induced by miR‐342‐5p. The expression of miR‐342‐5p was upregulated by transforming growth factor β, and inhibition of miR‐342‐5p attenuated the inhibitory effects of transforming growth factor β on lumen formation and sprouting by ECs. In addition, VEGF repressed miR‐342‐5p expression, and transfection of miR‐342‐5p repressed VEGFR2 and VEGFR3 expression and VEGF‐triggered Akt phosphorylation in ECs. miR‐342‐5p repressed angiogenesis in a laser‐induced choroidal neovascularization model in mice, highlighting its clinical potential.ConclusionsmiR‐342‐5p acts as a multifunctional angiogenic repressor mediating the effects and interaction among angiogenic pathways.

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“…Experimental studies confirmed the development of hypertension, proteinuria and histological lesions of PE in various organs in pregnant rats on infusion of recombinant adenovirus encoding sFlt-1 and sEng1. 6,7 Elevations in circulating sFlt-1 and sEng and reduction in PlGF levels antedate the appearance of PE. [8][9][10][11] This suggests that perturbation of other pathways may be necessary for the development of clinical manifestations.…”

Section: Introductionmentioning

confidence: 99%

The relationship between circulating endothelin-1, soluble fms-like tyrosine kinase-1 and soluble endoglin in preeclampsia

et al. 2011

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Placental overproduction of anti-angiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) has a key role in the development of preeclampsia (PE). Circulating endothelin-1 (ET-1) levels are also elevated in PE. In this study, we investigated the correlation between ET-1 and sFlt-1, placental growth factor (PlGF), sEng levels during uncomplicated normotensive pregnancy and PE. A total of 218 pregnant primigravid women were enrolled: 110 with PE and 108 uncomplicated normotensive pregnancies. PE was defined as new onset of elevated blood pressure (BP) 4140/90 mm Hg and X2 þ proteinuria on two occasions after 20 weeks of gestation in previously normotensive pregnant women. Circulating ET-1, sFlt-1, sEng and PlGF levels were estimated using enzyme immunoassays, and correlation between variables was ascertained. Women with PE showed higher levels of sFlt-1 (41.5 ± 15.7 vs 6.15 ± 3.4 ng ml -1 , Po0.001), sEng (84.9 ± 38.8 vs 13.2 ± 6.3 ng ml -1 , Po0.001), ET-1 (1.52 ± 0.55 vs 0.88±0.35 pg ml -1 , Po0.001) and sFlt-1:PlGF ratio (591.1±468.4 vs 18.3±2.1, Po0.001); and lower levels of PlGF (96.3 ± 47.2 vs 497.6 ± 328.2pg ml -1 , Po0.001). BP levels showed an independent relationship with sFlt-1:PlGF ratio in normotensive pregnant women and with sFlt-1:PlGF ratio and ET-1 in PE. sFlt-1 and sFlt-1:PlGF ratio correlated with proteinuria. ET-1 correlated significantly with sFlt-1, sEng and sFlt-1:PlGF ratio in PE. Our results show an association between elevation of sFlt-1 and sEng and ET-1 in the maternal circulation in PE, and strengthen the possibility that ET-1 may be a mediator in genesis of PE syndrome secondary to anti-angiogenic factors released by the placenta.

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Soluble endoglin contributes to the pathogenesis of preeclampsia

Cited by 1,642 publications

References 48 publications

Phenotypes of Pregnant Women Who Subsequently Develop Hypertension in Pregnancy

Phenotypes of Pregnant Women Who Subsequently Develop Hypertension in Pregnancy

miR‐342‐5p Is a Notch Downstream Molecule and Regulates Multiple Angiogenic Pathways Including Notch, Vascular Endothelial Growth Factor and Transforming Growth Factor β Signaling

The relationship between circulating endothelin-1, soluble fms-like tyrosine kinase-1 and soluble endoglin in preeclampsia

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