Endothelial responses to angiogenic modulators highlight metabolic mechanisms underlying vascular dysfunction in preeclampsia

Abstract

INTRODUCTION: An elevated sFlt-1/PlGF ratio in preeclampsia (PE) directly impairs endothelial cell (EC) metabolism, leading to increased lactate dehydrogenase (LDH) release, lipid peroxidation, and mitochondrial dysfunction. This may reflect a distinct metabolite profile which correlates with systemic maternal metabolic dysregulation, as evidenced by the association between circulating sFlt-1 and succinate/glycine levels. METHODS: A cross-sectional case-control study was performed on plasma of PE patients (n = 54) in addition to an in vitro study using ECs. We correlated plasma metabolite profiles (by nuclear magnetic resonance-based metabolomics) with sFlt-1 levels (by Enzyme-Linked Immunosorbent Assay). Mechanistically, we examined the impact of varying sFlt-1/PlGF ratios on EC function and metabolism after 24 h, assessing cell viability, cytotoxicity, proliferation, oxidative stress-related damage (lipid peroxidation and nitration), and real-time mitochondria function and metabolic profiles. RESULTS: In pregnant women with PE, circulating sFlt-1 levels positively correlated with succinate and glycine levels, but not significantly with lactate or glucose. In vitro, as sFlt-1/PlGF ratios, increased EC damage (LDH release) and oxidative stress-related damage (4-hydroxy-2-nonenal) increased dose-dependently. High sFlt-1/PlGF ratios also increased mitochondrial spare respiratory capacity, suggesting a compensatory mechanism. Metabolomics revealed metabolic reprogramming in ECs exposed to varying sFlt-1/PlGF ratios, with significant alterations in lactate, succinate, glucose, and glycine levels. DISCUSSION: These correlations and in vitro changes suggest a mechanistic link between sFlt-1/PlGF ratios, oxidative stress-related damage, and metabolic reprogramming in ECs, which could be targeted for therapeutics. Furthermore, the identification of succinate and glycine as key metabolites associated with sFlt-1 levels and sFlt-1/PlGF ratios may provide novel biomarkers for disease risk stratification and/or monitoring PE progression.