VEGF-R2/CAV-1 Interaction Induced by Resveratrol/Eicosapentaenoic Acid/Docosahexaenoic Acid-Enriched Formulation through Functional Detergent-Resistant Membranes Is Associated with Decreased VEGF-A Release in ARPE-19 Cells

Mol Nutr Food Res. 2024 Jun;68(11):e2300893. doi: 10.1002/mnfr.202300893. Epub 2024 May 19.

Abstract

Scope: Omega-3 fatty acids (O3FAs) and resveratrol (RSV) are known to be beneficial for certain eye diseases, such as age-related macular degeneration (AMD). Neovascular AMD is characterized by abnormal blood vessel formation due to the excessive synthesis of vascular endothelial growth factor (VEGF) by retinal pigment epithelium (RPE) cells. The study investigates whether a formulation based on eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and RSV is capable of counteracting VEGF-A secretion, and elucidates the molecular mechanism.

Methods and results: The study finds, using ELISA, that O3FAs/RSV reduces VEGF-A secretion in human RPE cells. This phenomenon is related to the increased interaction between VEGF-receptor 2 (VEGF-R2) and caveolin-1 (CAV-1), a protein of detergent-resistant membranes (DRMs), as determined by co-immunoprecipitation and proximity ligation assay. Using microscale thermophoresis, the study confirms that O3FAs/RSV causes a high-affinity interaction. Isolation and analysis of DRMs reveal that this interaction is concomitant with VEGF-R2 relocalization in DRMs. The depletion of DRMs by a cholesterol-chelating agent blocks the VEGF-R2/CAV-1 interaction and EPA/DHA/RSV-mediated impairment of VEGF production.

Conclusion: This specific interaction can provide a new strategy for countering VEGF-A production in human RPE cells and, consequently, reducing neovascularization in AMD. Further preclinical studies involving O3FAs and polyphenols are warranted.

Keywords: VEGF; VEGF‐receptor; angiogenesis; detergent‐resistant membranes; omega‐3 fatty acids; resveratrol.

MeSH terms

  • Caveolin 1* / metabolism
  • Cell Line
  • Docosahexaenoic Acids* / pharmacology
  • Eicosapentaenoic Acid* / pharmacology
  • Humans
  • Macular Degeneration / drug therapy
  • Macular Degeneration / metabolism
  • Resveratrol* / pharmacology
  • Retinal Pigment Epithelium* / drug effects
  • Retinal Pigment Epithelium* / metabolism
  • Vascular Endothelial Growth Factor A* / metabolism
  • Vascular Endothelial Growth Factor Receptor-2* / metabolism

Substances

  • Docosahexaenoic Acids
  • Eicosapentaenoic Acid
  • Vascular Endothelial Growth Factor A
  • Resveratrol
  • Caveolin 1
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor Receptor-2
  • CAV1 protein, human
  • KDR protein, human