Soluble Fms-like tyrosine kinase-1 alters cellular metabolism and mitochondrial bioenergetics in preeclampsia

Lissette Sanchez Aranguren , Cindy T. Espinosa-González, Laura M. González-Ortiz, Sandra M. Sanabria-Barrera, Carlos E. Riaño-Medina, Andrés F. Nuñez, Asif Ahmed, Jeannette Vasquez-Vivar, Marcos López*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article number83
JournalFrontiers in Physiology
Volume9
DOIs
Publication statusPublished - 6 Mar 2018

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Vascular Endothelial Growth Factor Receptor-1
Pre-Eclampsia
Energy Metabolism
Endothelial Cells
Trophoblasts
Galactose
Serum
Cell Respiration
Basal Metabolism
Mitochondrial Membrane Potential
First Pregnancy Trimester
Respiratory Rate
Proteinuria
Recombinant Proteins
Vascular Endothelial Growth Factor A
Reactive Oxygen Species
Mothers
Phenotype
Pregnancy

Bibliographical note

© 2018 Sánchez-Aranguren, Espinosa-González, González-Ortiz, Sanabria-Barrera, Riaño-Medina, Nuñez, Ahmed, Vasquez-Vivar and López. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Keywords

  • Endothelial dysfunction
  • Metabolism
  • Mitochondrial dysfunction
  • Oxidative stress and metabolic perturbations
  • Preeclampsia
  • SFlt-1

Cite this

Sanchez Aranguren , L., Espinosa-González, C. T., González-Ortiz, L. M., Sanabria-Barrera, S. M., Riaño-Medina, C. E., Nuñez, A. F., ... López, M. (2018). Soluble Fms-like tyrosine kinase-1 alters cellular metabolism and mitochondrial bioenergetics in preeclampsia. Frontiers in Physiology, 9, [83]. https://doi.org/10.3389/fphys.2018.00083
Sanchez Aranguren , Lissette ; Espinosa-González, Cindy T. ; González-Ortiz, Laura M. ; Sanabria-Barrera, Sandra M. ; Riaño-Medina, Carlos E. ; Nuñez, Andrés F. ; Ahmed, Asif ; Vasquez-Vivar, Jeannette ; López, Marcos. / Soluble Fms-like tyrosine kinase-1 alters cellular metabolism and mitochondrial bioenergetics in preeclampsia. In: Frontiers in Physiology. 2018 ; Vol. 9.
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abstract = "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.",
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Sanchez Aranguren , L, Espinosa-González, CT, González-Ortiz, LM, Sanabria-Barrera, SM, Riaño-Medina, CE, Nuñez, AF, Ahmed, A, Vasquez-Vivar, J & López, M 2018, 'Soluble Fms-like tyrosine kinase-1 alters cellular metabolism and mitochondrial bioenergetics in preeclampsia', Frontiers in Physiology, vol. 9, 83. https://doi.org/10.3389/fphys.2018.00083

Soluble Fms-like tyrosine kinase-1 alters cellular metabolism and mitochondrial bioenergetics in preeclampsia. / Sanchez Aranguren , Lissette; Espinosa-González, Cindy T.; González-Ortiz, Laura M.; Sanabria-Barrera, Sandra M.; Riaño-Medina, Carlos E.; Nuñez, Andrés F.; Ahmed, Asif; Vasquez-Vivar, Jeannette; López, Marcos.

In: Frontiers in Physiology, Vol. 9, 83, 06.03.2018.

Research output: Contribution to journalArticle

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AU - Sanchez Aranguren , Lissette

AU - Espinosa-González, Cindy T.

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AU - Sanabria-Barrera, Sandra M.

AU - Riaño-Medina, Carlos E.

AU - Nuñez, Andrés F.

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AU - Vasquez-Vivar, Jeannette

AU - López, Marcos

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AB - 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.

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Sanchez Aranguren L, Espinosa-González CT, González-Ortiz LM, Sanabria-Barrera SM, Riaño-Medina CE, Nuñez AF et al. Soluble Fms-like tyrosine kinase-1 alters cellular metabolism and mitochondrial bioenergetics in preeclampsia. Frontiers in Physiology. 2018 Mar 6;9. 83. https://doi.org/10.3389/fphys.2018.00083