1. Academic Validation
  2. ( R, S)-Equol 7-β-D-glucuronide, but not other circulating isoflavone metabolites, modulates migration and tubulogenesis in human aortic endothelial cells targeting the VEGF pathway

( R, S)-Equol 7-β-D-glucuronide, but not other circulating isoflavone metabolites, modulates migration and tubulogenesis in human aortic endothelial cells targeting the VEGF pathway

  • Food Funct. 2023 Dec 11. doi: 10.1039/d3fo03946c.
Juan Antonio Giménez-Bastida 1 María Ángeles Ávila-Gálvez 1 2 Alicia Martínez-López 3 4 Diana García-Moreno 3 4 Juan Carlos Espín 1 Antonio González-Sarrías 1
Affiliations

Affiliations

  • 1 Laboratory of Food & Health, Research Group on Quality, Safety and Bioactivity of Plant Foods, CEBAS-CSIC, Murcia, Spain. jgbastida@cebas.csic.es.
  • 2 NOVA Medical School
  • 3
  • 4
  • 5 Center for Biomedical Research in Rare Diseases Network (CIBERER), Carlos III Health Institute, 28029, Madrid, Spain.
  • 6 Biomedical Research Institute of Murcia (IMIB)-Pascual Parrilla, 30120, Murcia, Spain.
Abstract

Current knowledge indicates that the consumption of isoflavone-rich foodstuffs can have a beneficial impact on cardiovascular health. To what extent these Isoflavones act as the main actors of that benefit is less clear. Genistein (GEN), daidzein (DAZ), and the DAZ-derived microbial metabolite equol (Eq) exhibit antiangiogenic effects in vitro, but their low bloodstream concentrations make it difficult to rationalize the in vivo effects. Their derived phase-II metabolites (glucuronides and sulfates) are major metabolites found in plasma, but their role as antiangiogenic molecules remains unexplored. We aimed here to first assess the anti-angiogenic activities of the main circulating isoflavone metabolites (glucuronides and sulfates) and compare them with their corresponding free forms at physiological concentrations (0.1-10 μM). The effects of the conjugated vs. free forms on tubulogenesis, cell migration, and VEGF-induced signalling were investigated in primary human aortic endothelial cells (HAECs). While (R,S)-equol 7-β-D-glucuronide (Eq 7-glur) exerted dose-dependent inhibition of tubulogenesis and endothelial migration comparable to that exerted by the free forms (GEN, DAZ, and Eq), the rest of the phase-II conjugates exhibited no significant effects. The underlying molecular mechanisms were independent of the bFGF but related to the modulation of the VEGF pathway. Besides, the observed dissimilar cellular metabolism (conjugation/deconjugation) places the phase-II metabolites as precursors of the free forms; however, the question of whether this metabolism impacts their biological activity requires additional studies. These new insights suggest that Isoflavones and their circulating metabolites, including Eq 7-glur, may be involved in cardiovascular health (e.g., targeting angiogenesis).

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