Epoxyeicosatrienoic acid (EET)-stimulated angiogenesis is mediated by epoxy hydroxyeicosatrienoic acids (EHETs) formed from COX-2

J Lipid Res. 2019 Dec;60(12):1996-2005. doi: 10.1194/jlr.M094219. Epub 2019 Oct 22.


Epoxyeicosatrienoic acids (EETs) are formed from the metabolism of arachidonic acid by cytochrome P450s. EETs promote angiogenesis linked to tumor growth in various cancer models that is attenuated in vivo by cyclooxygenase 2 (COX-2) inhibitors. This study further defines a role for COX-2 in mediating endothelial EET metabolism promoting angiogenesis. Using human aortic endothelial cells (HAECs), we quantified 8,9-EET-induced tube formation and cell migration as indicators of angiogenic potential in the presence and absence of a COX-2 inducer [phorbol 12,13-dibutyrate (PDBu)]. The angiogenic response to 8,9-EET in the presence of PDBu was 3-fold that elicited by 8,9-EET stabilized with a soluble epoxide hydrolase inhibitor (t-TUCB). Contributing to this response was the COX-2 metabolite of 8,9-EET, the 11-hydroxy-8,9-EET (8,9,11-EHET), which exogenously enhanced angiogenic responses in HAECs at levels comparable to those elicited by vascular endothelial growth factor (VEGF). In contrast, the 15-hydroxy-8,9-EET isomer was also formed but inactive. The 8,9,11-EHET also promoted expression of the VEGF family of tyrosine kinase receptors. These results indicate that 8,9-EET-stimulated angiogenesis is enhanced by COX-2 metabolism in the endothelium through the formation of 8,9,11-EHET. This alternative pathway for the metabolism of 8,9-EET may be particularly important in regulating angiogenesis under circumstances in which COX-2 is induced, such as in cancer tumor growth and inflammation.

Keywords: angiogenesis; arachidonic acid; cancer; cyclooxygenase 2; endothelial cells; mass spectrometry; metabolism; soluble epoxide hydrolase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inducing Agents / pharmacology*
  • Cyclooxygenase 2 / metabolism*
  • Cycloparaffins / pharmacology*
  • Eicosanoids / metabolism*
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Humans
  • Receptors, Vascular Endothelial Growth Factor / metabolism


  • Angiogenesis Inducing Agents
  • Cycloparaffins
  • Eicosanoids
  • epoxyethylcyclooctane
  • Cyclooxygenase 2
  • Receptors, Vascular Endothelial Growth Factor