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: 0301 basic medicine; Biochemistry & Molecular Biology; 610; QD415-436; soluble epoxide hydrolase; Medical Biochemistry and Metabolomics; Cardiovascular; Biochemistry; angiogenesis; 03 medical and health sciences; Receptors; arachidonic acid; 2.1 Biological and endogenous factors; Medical biochemistry and metabolomics; cancer; Humans; cyclooxygenase 2; Cancer; mass spectrometry; Biomedical and Clinical Sciences; Vascular Endothelial Growth Factor; Endothelial Cells; Cycloparaffins; Biological Sciences; endothelial cells; Receptors, Vascular Endothelial Growth Factor; Cyclooxygenase 2; Biochemistry and cell biology; Eicosanoids; Angiogenesis Inducing Agents; Biochemistry and Cell Biology; metabolism

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.