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Biomarkers of Oxidative Stress

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Front. Physiol. | doi: 10.3389/fphys.2018.00083

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

 Lissette C. Sanchez-Aranguren1, 2, Cindy T. Espinosa-Gonzalez1, Laura M. Gonzalez-Ortiz1, 2,  Sandra M. Sanabria-Barrera1, 2,  Carlos E. Riaño1, 3, 4, Andres F. Nuñez5,  Asif Ahmed6,  Jeannette Vasquez-Vivar7 and  Marcos Lopez1, 2*
  • 1Translational Biomedical Research Group, Fundación Cardiovascular de Colombia, Colombia
  • 2Graduate Program in Biomedical Sciences, Faculty of Health, University of Valle, Colombia
  • 3Maternal-Fetal Medicine Unit, Fundación Cardiovascular de Colombia, Colombia
  • 4Meternal Fetal Unit, Hospital Internacional de Colombia (HIC), Colombia
  • 5Maternal Fetal Unit, Clinica San Luis, Colombia
  • 6Aston Medical School, Aston University, Birmingham, United Kingdom
  • 7Department of Biophysics, Medical College of Wisconsin, United States

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 circulating 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 sFTL-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 sFtl or with the recombinant protein. sFlt-1, dose-dependently inhibited ECs respiration and acidification rates indicating ametabolic phenotype switch enhancing glycolytic flux. HTR-8/SVneo displayed a strong basal glycolytic metabolism, remaining less sensitive to sFlt-1-induced mitochondrial impairment. Moreover, ECs exposed to serum from preeclamptic subjects demonstrated that increased sFtl1 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. The effects of sFlt-1 on HTR-8/SVneo cells metabolism was amplified in galactose, demonstrating that sFlt-1 will only target cells that rely mainly on oxidative metabolism.. Together these findings indicate sFTl1 mediates of oxidative stress and loss of function predominantly in ECs, which maybe a significant event in sFtl1 preeclampsia mechanisms.

Keywords: Preeclampsia, sFlt-1, Mitochondrial dysfunction, endothelial dysfunction, Oxidative Stress, Mitochondria, Metabolism and bioenergetics, glycolysis and oxidative phosphorylation, perturbations, Placenta, Pregnancy induced hypertension

Received: 25 Nov 2017; Accepted: 23 Jan 2018.

Edited by:

Sruti Shiva, University of Pittsburgh, United States

Reviewed by:

Saurabh Aggarwal, University of Alabama at Birmingham, United States
Bo Akerstrom, Lund University, Sweden  

Copyright: © 2018 Sanchez-Aranguren, Espinosa-Gonzalez, Gonzalez-Ortiz, Sanabria-Barrera, Riaño, Nuñez, Ahmed, Vasquez-Vivar and Lopez. 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.

* Correspondence: Dr. Marcos Lopez, Fundación Cardiovascular de Colombia, Translational Biomedical Research Group, Cra 5a No. 6-33, Floridablanca, 681003, Santander, Colombia, marco4357@gmail.com