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Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia.

ABSTRACT: Preeclampsia, a syndrome affecting 5% of pregnancies, causes substantial maternal and fetal morbidity and mortality. The pathophysiology of preeclampsia remains largely unknown. It has been hypothesized that placental ischemia is an early event, leading to placental production of a soluble factor or factors that cause maternal endothelial dysfunction, resulting in the clinical findings of hypertension, proteinuria, and edema. Here, we confirm 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 sFlt1 that fall after delivery. We demonstrate that increased circulating sFlt1 in patients with preeclampsia is associated with decreased circulating levels of free VEGF and PlGF, resulting in endothelial dysfunction in vitro that can be rescued by exogenous VEGF and PlGF. Additionally, VEGF and PlGF cause microvascular relaxation of rat renal arterioles in vitro that is blocked by sFlt1. Finally, administration of sFlt1 to pregnant rats induces hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia. These observations suggest that excess circulating sFlt1 contributes to the pathogenesis of preeclampsia.

SUBMITTER: Maynard SE

PROVIDER: S-EPMC151901 | biostudies-literature | 2003 Mar

REPOSITORIES: biostudies-literature

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Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia.

Maynard Sharon E SE Min Jiang-Yong JY Merchan Jaime J Lim Kee-Hak KH Li Jianyi J Mondal Susanta S Libermann Towia A TA Morgan James P JP Sellke Frank W FW Stillman Isaac E IE Epstein Franklin H FH Sukhatme Vikas P VP Karumanchi S Ananth SA

The Journal of clinical investigation 20030301 5

Preeclampsia, a syndrome affecting 5% of pregnancies, causes substantial maternal and fetal morbidity and mortality. The pathophysiology of preeclampsia remains largely unknown. It has been hypothesized that placental ischemia is an early event, leading to placental production of a soluble factor or factors that cause maternal endothelial dysfunction, resulting in the clinical findings of hypertension, proteinuria, and edema. Here, we confirm that placental soluble fms-like tyrosine kinase 1 (sF ...[more]

PMID: 12618519

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Project description:Background: Aim of the study was a critical assessment of the clinical validity of the prenatal determination of sFlt-1/PlGF for preeclampsia (PE), pregnancy-induced hypertension (PIH), and proteinuria. Our analysis was based on a specificity of 95 % and a sensitivity of 82 % for the prediction of preeclampsia, as described by Elecsys (Roche). Methods: In this retrospective study the ratio of the prenatal antiangiogenic factor sFlt-1 (soluble fms-like tyrosine kinase-1) to the proangiogenic factor PIGF (placental growth factor) was analyzed using the electrochemiluminescence immunoassay of Elecsys (Roche Diagnostics, Mannheim, Germany) in 173 pregnant women. Sixty-three women with PE, 34 women with PIH and 6 women with proteinuria were compared to 72 controls. On average, the sFlt-1/PlGF ratio was determined 8 (controls), 2.4 (PE), 3.2 (PIH) and 4.1 (proteinuria) weeks before delivery. The PE and PIH cases were further subdivided into early (< 34 weeks of gestation) and late (≥ 34 weeks of gestation) onset groups. Statistical data analysis was done using the usual descriptive statistics and logistic regression analysis. ROC curves were calculated, and the sensitivity, specificity, and negative and positive predictive value (NPV, PPV) were estimated for a threshold of 85. Results: Although the specificity of the sFlt-1/PlGF ratio was high for PE, the sensitivity was low (only 59.4 %), thus giving unsatisfying results for PE. The sensitivity only increased to 62.5 % for the early-onset PE group. Intriguingly, a high ratio was detected for the combination of IUGR (intrauterine growth restriction) and PE in the early-onset PE group (8 cases). In the control group, 4 cases exceeded the cut-off value of 85 but showed no clinical signs of PE and the birth was unremarkable. In summary, we found that the sFlt-1/PIGF ratio could not be used as a predictive test for preeclampsia but rather as an indicator for the development and estimation of the severity of PE. Thus, the test is less suitable for the reliable exclusion of PE in routine clinical practice. Recommendation: The determination of the sFlT-1/PlGF ratio is only one element for PE diagnosis in addition to the measurement of blood pressure, proteinuria, ultrasound and Doppler.

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.

Dataset Information

Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia.

Publications

Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia.

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