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

• DOI: 10.1194/jlr.m094219
• Publication Date: 2019-10-22T21:44:07Z
• Authors: Amy A. Rand; Anita Rajamani; Sean D. Kodani; Todd R. Harris; Lukas Schlatt; Bodgan Barnych; Anthony G. Passerini; Bruce D. Hammock
• Keywords: Epoxyeicosatrienoic acid; Epoxide hydrolase 2; Hydroxyeicosatetraenoic acid

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