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Transcriptionally active syncytial aggregates in the maternal circulation may contribute to circulating soluble fms-like tyrosine kinase 1 in preeclampsia.

ABSTRACT: The cardinal manifestations of the pregnancy-specific disorder preeclampsia, new-onset hypertension, and proteinuria that resolve with placental delivery have been linked to an extracellular protein made by the placenta, soluble fms-like tyrosine kinase 1 (sFlt1), that injures the maternal vasculature. However, the mechanisms by which sFlt1, which is heavily matrix bound, gain access to the systemic circulation remain unclear. Here we report that the preeclamptic placenta's outermost layer, the syncytiotrophoblast, forms abundant "knots" that are enriched with sFlt1 protein. These syncytial knots easily detach from the syncytiotrophoblast, resulting in free, multinucleated aggregates (50-150 ?m diameter) that are loaded with sFlt1 protein and mRNA, are metabolically active, and are capable of de novo gene transcription and translation. At least 25% of the measurable sFlt1 in the third-trimester maternal plasma is bound to circulating placental microparticles. We conclude that detachment of syncytial knots from the placenta results in free, transcriptionally active syncytial aggregates that represent an autonomous source of sFlt1 delivery into the maternal circulation. The process of syncytial knot formation, shedding of syncytial aggregates, and appearance of placental microparticles in the maternal circulation appears to be greatly accelerated in preeclampsia and may contribute to the maternal vascular injury that characterizes this disorder.

SUBMITTER: Rajakumar A

PROVIDER: S-EPMC3319764 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Transcriptionally active syncytial aggregates in the maternal circulation may contribute to circulating soluble fms-like tyrosine kinase 1 in preeclampsia.

Rajakumar Augustine A Cerdeira Ana Sofia AS Rana Sarosh S Zsengeller Zsuzsanna Z Edmunds Lia L Jeyabalan Arun A Hubel Carl A CA Stillman Isaac E IE Parikh Samir M SM Karumanchi S Ananth SA

Hypertension (Dallas, Tex. : 1979) 20120103 2

The cardinal manifestations of the pregnancy-specific disorder preeclampsia, new-onset hypertension, and proteinuria that resolve with placental delivery have been linked to an extracellular protein made by the placenta, soluble fms-like tyrosine kinase 1 (sFlt1), that injures the maternal vasculature. However, the mechanisms by which sFlt1, which is heavily matrix bound, gain access to the systemic circulation remain unclear. Here we report that the preeclamptic placenta's outermost layer, the ...[more]

PMID: 22215706

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Project description:Preeclampsia is a maternal hypertensive disorder that affects up to 1 out of 12 pregnancies worldwide. It is characterized by proteinuria, endothelial dysfunction, and elevated levels of the soluble form of the vascular endothelial growth factor receptor-1 (VEGFR-1, known as sFlt-1). sFlt-1 effects are mediated in part by decreasing VEGF signaling. The direct effects of sFlt-1 on cellular metabolism and bioenergetics in preeclampsia, have not been established. The goal of this study was to evaluate whether sFlt-1 causes mitochondrial dysfunction leading to disruption of normal functioning in endothelial and placental cells in preeclampsia. Endothelial cells (ECs) and first-trimester trophoblast (HTR-8/SVneo) were treated with serum from preeclamptic women rich in sFlt-1 or with the recombinant protein. sFlt-1, dose-dependently inhibited ECs respiration and acidification rates indicating a metabolic phenotype switch enhancing glycolytic flux. HTR-8/SVneo displayed a strong basal glycolytic metabolism, remaining less sensitive to sFlt-1-induced mitochondrial impairment. Moreover, results obtained in ECs exposed to serum from preeclamptic subjects demonstrated that increased sFlt-1 leads to metabolic perturbations accountable for mitochondrial dysfunction observed in preeclampsia. sFlt-1 exacerbated mitochondrial reactive oxygen species (ROS) formation and mitochondrial membrane potential dissipation in ECs and trophoblasts exposed to serum from preeclamptic women. Forcing oxidative metabolism by culturing cells in galactose media, further sensitized cells to sFlt-1. This approach let us establish that sFlt-1 targets mitochondrial function in ECs. Effects of sFlt-1 on HTR-8/SVneo cells metabolism were amplified in galactose, demonstrating that sFlt-1 only target cells that rely mainly on oxidative metabolism. Together, our results establish the early metabolic perturbations induced by sFlt-1 and the resulting endothelial and mitochondrial dysfunction in preeclampsia.

Project description:Preeclampsia (PE) is a life-threatening hypertensive disorder during pregnancy associated with decreased circulating aldosterone levels. However, the molecular mechanisms underlying aldosterone reduction in PE remain unidentified. Here we demonstrate that reduced circulating aldosterone levels in preeclamptic women are associated with the presence of angiotensin II type 1 receptor agonistic autoantibody and elevated soluble Fms-like tyrosine kinase-1, 2 prominent pathogenic factors in PE. Using an adoptive transfer animal model of PE, we provide in vivo evidence that the injection of IgG from women with PE, but not IgG from normotensive individuals, resulted in hypertension, proteinuria, and a reduction in aldosterone production from 1377 ± 272 pg/mL to 544 ± 92 pg/mL (P<0.05) in pregnant mice. These features were prevented by coinjection with an epitope peptide that blocks antibody-mediated angiotensin type 1 receptor activation. In contrast, injection of IgG from preeclamptic women into nonpregnant mice induced aldosterone levels from 213 ± 24 pg/mL to 615 ± 48 pg/mL (P<0.05). These results indicate that maternal circulating autoantibody in preeclamptic women is a detrimental factor causing decreased aldosterone production via angiotensin type 1 receptor activation in a pregnancy-dependent manner. Next, we found that circulating soluble Fms-like tyrosine kinase-1 was only induced in autoantibody-injected pregnant mice but not nonpregnant mice. As such, we further observed vascular impairment in adrenal glands of pregnant mice. Finally, we demonstrated that infusion of vascular endothelial growth factor(121) attenuated autoantibody-induced adrenal gland vascular impairment resulting in a recovery in circulating aldosterone (from 544 ± 92 to 1110 ± 269 pg/mL; P<0.05). Overall, we revealed that angiotensin II type 1 receptor agonistic autoantibody-induced soluble Fms-like tyrosine kinase-1 elevation is a novel pathogenic mechanism underlying decreased aldosterone production in PE.

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Transcriptionally active syncytial aggregates in the maternal circulation may contribute to circulating soluble fms-like tyrosine kinase 1 in preeclampsia.

Publications

Transcriptionally active syncytial aggregates in the maternal circulation may contribute to circulating soluble fms-like tyrosine kinase 1 in preeclampsia.

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