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A recently evolved novel trophoblast-enriched secreted form of fms-like tyrosine kinase-1 variant is up-regulated in hypoxia and preeclampsia.

ABSTRACT: Recent published studies indicate a possible role for sFlt1 in the development of preeclampsia.The objective of the study was to investigate the expression and regulation of sFlt1-e15a, a recently described novel C-terminal variant isoform of sFlt1.The studies included a computational comparative analysis of the genomic locus of sFlt1 across vertebrate species; an assessment of sFlt1 variants in human and rhesus cells and tissues; an analysis of sFlt1 variants transiently expressed in HeLa and COS-7 cells; an evaluation of the effect of hypoxia on sFlt1 expression in trophoblasts; and a comparison of placental sFlt1 expression between pregnancies complicated by preeclampsia and control pregnancies.sFlt1-e15a emerged as an alternate transcript of Flt1 late in evolution with the insertion of an AluSq sequence into the primate genome after the emergence of the simian infraorder about 40 million years ago. sFlt1-e15a is particularly abundant in human placenta and trophoblasts and is also highly expressed in nonhuman primate placenta. The expressed protein has a C-terminal polyserine tail and, like reference sequence sFlt1 (sFlt1-i13), is glycosylated and secreted. Consistent with a role in placental pathophysiology, hypoxia stimulates sFlt1-e15a expression in isolated cytotrophoblasts and a trophoblast cell line, and differentiation into syncytiotrophoblasts further enhances the effect of hypoxia. Placental levels of sFlt1-e15a and sFlt1-i13 transcripts are significantly elevated in patients with preeclampsia compared with normal pregnancies. We speculate that sFlt1-e15a may contribute to the pathophysiology of preeclampsia.

SUBMITTER: Thomas CP

PROVIDER: S-EPMC2708964 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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A recently evolved novel trophoblast-enriched secreted form of fms-like tyrosine kinase-1 variant is up-regulated in hypoxia and preeclampsia.

Thomas Christie P CP Andrews Janet I JI Raikwar Nandita S NS Kelley Elizabeth A EA Herse Florian F Dechend Ralf R Golos Thaddeus G TG Liu Kang Z KZ

The Journal of clinical endocrinology and metabolism 20090331 7

<h4>Context</h4>Recent published studies indicate a possible role for sFlt1 in the development of preeclampsia.<h4>Objective</h4>The objective of the study was to investigate the expression and regulation of sFlt1-e15a, a recently described novel C-terminal variant isoform of sFlt1.<h4>Design</h4>The studies included a computational comparative analysis of the genomic locus of sFlt1 across vertebrate species; an assessment of sFlt1 variants in human and rhesus cells and tissues; an analysis of s ...[more]

PMID: 19336504

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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.

Dataset Information

A recently evolved novel trophoblast-enriched secreted form of fms-like tyrosine kinase-1 variant is up-regulated in hypoxia and preeclampsia.

Publications

A recently evolved novel trophoblast-enriched secreted form of fms-like tyrosine kinase-1 variant is up-regulated in hypoxia and preeclampsia.

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