Enhanced Endothelin Synthesis by Endothelial Cells Exposed to Sera From Pregnant Rats With Decreased Uterine Perfusion

Roberts, Lyndsay; LaMarca, Babbette; Fournier, Lillian; Bain, Jennifer; Cockrell, Kathy; Granger, Joey P.

doi:10.1161/01.hyp.0000197950.42301.dd

Cited by 73 publications

(86 citation statements)

References 19 publications

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“…Exposure of human umbilical vein endothelial cell cultures to sera collected from reductions in uteroplacental perfusion pressure was followed by an increase in the ET-1 concentration in the media, whereas no such increase was noted when cells were exposed to sera from normal pregnant rats, suggesting that a substance present in the PE sera induced ET-1 synthesis. 21 In other studies, hypertension produced by placental ischemia in pregnant rats has been shown to be associated with increased sFlt-1 and sEng levels. 22,23 In this study, ET-1 levels showed a significant correlation with sFlt-1, sEng and sFlt-1:PlGF ratio in PE, but not in the N group.…”

Section: Discussionmentioning

confidence: 88%

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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Section: Discussionmentioning

confidence: 88%

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

et al. 2011

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“…ET-1, however, is produced locally in the vasculature and plasma levels typically do not reflect tissue levels of the peptide. Local renal and endothelial production of ET-1 is exaggerated in placental ischemic conditions (121,148). We have shown that the hypertensive responses to infusion of the soluble placental ischemia factors TNF-␣, AT1-AA, or sFlt-1 into normal pregnant rats and in response to RUPP are prevented by antagonism of the ET A receptor (88,93,121,177).…”

Section: Effects Of Obesity On Placental Ischemia-induced Endothelialmentioning

confidence: 98%

Increased risk for the development of preeclampsia in obese pregnancies: weighing in on the mechanisms

Spradley

Palei

Granger

2015

American Journal of Physiology-Regulatory, Integrative and Comp

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115

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) is a pregnancy-specific disorder typically presenting as new-onset hypertension and proteinuria. While numerous epidemiological studies have demonstrated that obesity increases the risk of PE, the mechanisms have yet to be fully elucidated. Growing evidence from animal and human studies implicate placental ischemia in the etiology of this maternal syndrome. It is thought that placental ischemia is brought about by dysfunctional cytotrophoblast migration and invasion into the uterus and subsequent lack of spiral arteriole widening and placental perfusion. Placental ischemia/ hypoxia stimulates the release of soluble placental factors into the maternal circulation where they cause endothelial dysfunction, particularly in the kidney, to elicit the clinical manifestations of PE. The most recognized of these factors are the anti-angiogenic sFlt-1 and pro-inflammatory TNF-␣ and AT1-AA, which promote endothelial dysfunction by reducing levels of the provasodilator nitric oxide and stimulating production of the potent vasoconstrictor endothelin-1 and reactive oxygen species. We hypothesize that obesity-related metabolic factors increase the risk for developing PE by impacting various stages in the pathogenesis of PE, namely, 1) cytotrophoblast migration and placental ischemia; 2) release of soluble placental factors into the maternal circulation; and 3) maternal endothelial and vascular dysfunction. This review will summarize the current experimental evidence supporting the concept that obesity and metabolic factors like lipids, insulin, glucose, and leptin affect placental function and increase the risk for developing hypertension in pregnancy by reducing placental perfusion; enhancing placental release of soluble factors; and by increasing the sensitivity of the maternal vasculature to placental ischemia-induced soluble factors. body mass index; inflammation; placental ischemia; pregnancy; RUPP; sFlt-1 PE IS A PREGNANCY-SPECIFIC DISORDER typically identified by new-onset hypertension in the second half of pregnancy. Although often accompanied by new-onset proteinuria, PE can be associated with many other signs and symptoms including headaches, visual disturbances, epigastric pain, and the development of edema (4,192). Globally, this disease affects over 8 million pregnancies per year and is estimated to account for 40 -60% of maternal deaths in developing countries (125). In the United States, there was a 25% increase in the rate of PE between the years 1987-2004 (189). This significant increase highlights the importance of understanding how risk factors like obesity play a role in the pathogenesis of this maternal syndrome. Obesity is defined as a body mass index (BMI) of greater than or equal to 30 kg/m 2 . Greater than one-half of pregnant women are overweight or obese (48), and more than two-thirds of reproductive-aged women in the United States are overweight or obese (49). Although mounting epidemiological evidence supports obesity as a major risk factor for PE, the mechanisms linking these two morbidities are...

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“…49 The exact mechanism linking enhanced renal production of ET-1 to placental ischemia in pregnant rats or in preeclamptic women is unknown. One potential mechanism for enhanced ET-1 production is via transcriptional regulation of the ET-1 gene by TNF-␣.…”

Section: Endothelinmentioning

confidence: 99%

Recent Progress Toward the Understanding of the Pathophysiology of Hypertension During Preeclampsia

2008

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Enhanced Endothelin Synthesis by Endothelial Cells Exposed to Sera From Pregnant Rats With Decreased Uterine Perfusion

Cited by 73 publications

References 19 publications

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

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

Increased risk for the development of preeclampsia in obese pregnancies: weighing in on the mechanisms

Recent Progress Toward the Understanding of the Pathophysiology of Hypertension During Preeclampsia

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