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

doi:10.3389/fphys.2018.00083

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

Fundación Cardiovascular de Colombia
Universidad del Valle
Clínica Materno Infantil San Luis
King Abdulaziz University
Medical College of Wisconsin

Research output: Contribution to journal › Article › peer-review

35 Citations (Scopus)

108 Downloads (Pure)

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 language	English
Article number	83
Journal	Frontiers in Physiology
Volume	9
DOIs	https://doi.org/10.3389/fphys.2018.00083
Publication status	Published - 6 Mar 2018

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.

Funding

We will like to thank the stafffrom FCV and CMISL for their support during patient recruitment. We are also grateful to Drs. Balaraman Kalyanaraman and Jacek Zielonka from the Free Radical Research Center from the Department of Biophysics of the Medical College of Wisconsin for their help and guidance. This work was supported by the Administrative Department for Science, Technology and Innovation of Colombia, (COLCIENCIAS) grants: [CT470-2012 to ML, CR-M, and LS-A, CT477-2012 and CT734-2013 to ML], and by the National Institutes of Health [NS081936 to JV-V].

Keywords

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

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10.3389/fphys.2018.00083Licence: CC BY 3.0

Soluble Fms-Like Tyrosine Kinase-1
© 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.
Final published version, 2.72 MBLicence: CC BY 3.0

Cite this

Sanchez Aranguren , L., Espinosa-González, C. T., González-Ortiz, L. M., Sanabria-Barrera, S. M., Riaño-Medina, C. E., Nuñez, A. F., 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, 9, Article 83. https://doi.org/10.3389/fphys.2018.00083

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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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AU - Sanabria-Barrera, Sandra M.

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AU - Nuñez, Andrés F.

AU - Ahmed, Asif

AU - Vasquez-Vivar, Jeannette

AU - López, Marcos

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ER -

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

Abstract

Bibliographical note

Funding

Keywords

Access to Document

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