Mediterranean diet polyphenols reduce inflammatory angiogenesis through MMP-9 and COX-2 inhibition in human vascular endothelial cells: a potentially protective mechanism in atherosclerotic vascular disease and cancer

Arch Biochem Biophys. 2012 Nov 15;527(2):81-9. doi: 10.1016/ Epub 2012 May 14.


Diets with high content of antioxidant polyphenols are associated with low prevalence of cardiovascular diseases and cancer. Inflammatory angiogenesis is a key pathogenic process both in cancer and atherosclerosis, and is tightly regulated by the proinflammatory enzyme cyclooxygenase (COX)-2 and the matrix degrading enzymes matrix metalloproteinases (MMPs). We studied the effects of antioxidant polyphenols from virgin olive oil (oleuropein and hydroxytyrosol) and red wine (resveratrol and quercetin) on endothelial cell angiogenic response in vitro, and explored underlying mechanisms. Cultured endothelial cells were pre-incubated with 0.1-50 μmol/L polyphenols before stimulation with phorbol myristate acetate (PMA). All tested polyphenols reduced endothelial cell tube formation on matrigel and migration in wound healing assays. The reduced angiogenesis was associated with the inhibition of PMA-induced COX-2 protein expression and prostanoid production, as well as MMP-9 protein release and gelatinolytic activity. These effects were accompanied by a significant reduction in the stimulated intracellular reactive oxygen species levels and in the activation of the redox-sensitive transcription factor nuclear factor (NF)-κB. Our findings reveal that olive oil and red wine polyphenols reduce inflammatory angiogenesis in cultured endothelial cells, through MMP-9 and COX-2 inhibition, supporting a potential protective role for dietary polyphenols in atherosclerotic vascular disease and cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / pharmacology
  • Antioxidants / therapeutic use
  • Atherosclerosis / prevention & control*
  • Cyclooxygenase 2 / metabolism*
  • Cyclooxygenase 2 Inhibitors / pharmacology
  • Cyclooxygenase 2 Inhibitors / therapeutic use
  • Diet, Mediterranean*
  • Gene Expression Regulation, Enzymologic / drug effects
  • Human Umbilical Vein Endothelial Cells / drug effects*
  • Human Umbilical Vein Endothelial Cells / enzymology
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Inflammation / physiopathology
  • Matrix Metalloproteinase 9 / metabolism*
  • Matrix Metalloproteinase Inhibitors / pharmacology
  • Matrix Metalloproteinase Inhibitors / therapeutic use
  • NF-kappa B / metabolism
  • Neoplasms / prevention & control*
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / enzymology
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Olive Oil
  • Plant Oils / chemistry
  • Polyphenols / pharmacology*
  • Polyphenols / therapeutic use
  • Reactive Oxygen Species / metabolism
  • Tetradecanoylphorbol Acetate / pharmacology
  • Wine / analysis


  • Antioxidants
  • Cyclooxygenase 2 Inhibitors
  • Matrix Metalloproteinase Inhibitors
  • NF-kappa B
  • Olive Oil
  • Plant Oils
  • Polyphenols
  • Reactive Oxygen Species
  • Cyclooxygenase 2
  • Matrix Metalloproteinase 9
  • Tetradecanoylphorbol Acetate