Cytochrome P450 2C9-derived epoxyeicosatrienoic acids induce angiogenesis via cross-talk with the epidermal growth factor receptor (EGFR). FASEB J 2003 Apr;17(6):770-2
Date
02/15/2003Pubmed ID
12586744DOI
10.1096/fj.02-0640fjeScopus ID
2-s2.0-0037387681 (requires institutional sign-in at Scopus site) 159 CitationsAbstract
Cytochrome P450 (CYP) epoxygenase products, such as 11,12-epoxyeicosatrienoic acid (EET), stimulate endothelial cell proliferation. We set out to identify the signal transduction cascade linking EET generation to enhanced proliferation and angiogenesis. In human endothelial cells overexpressing CYP 2C9, cell number was increased compared with control cells and was inhibited by the CYP 2C9 inhibitor, sulfaphenazole. CYP 2C9 overexpression was associated with the activation of Akt and an increase in cyclin D1 expression, effects that were abolished by the epidermal growth factor (EGF) receptor inhibitor, AG1478, which also prevented the CYP 2C9-induced increase in cell proliferation. Stimulation of EGF receptor overexpressing cells with 11,12-EET or transfection of these cells with CYP 2C9 enhanced the tyrosine phosphorylation of the EGF receptor. Endothelial tube formation in a fibrin gel was significantly enhanced (6-fold) in CYP 2C9 overexpressing cells and was comparable with the tube formation induced by EGF. In the chick chorioallantoic membrane, 11,12-EET stimulated vessel formation (3.5-fold) and induced vessel convergence, an effect that was abolished by cotreatment with either an EGF receptor-neutralizing antibody or AG1478. These results indicate that CYP 2C9-derived EETs stimulate angiogenesis by a mechanism involving the activation of the EGF receptor.
Author List
Michaelis UR, Fisslthaler B, Medhora M, Harder D, Fleming I, Busse RAuthor
Meetha Medhora Professor in the Radiation Oncology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
8,11,14-Eicosatrienoic AcidAllantois
Animals
Aryl Hydrocarbon Hydroxylases
Cell Division
Cell Line
Chick Embryo
Chorion
Cyclin D1
Cytochrome P-450 CYP2C9
Endothelium, Vascular
Enzyme Inhibitors
ErbB Receptors
Humans
Neovascularization, Physiologic
Phosphorylation
Protein Tyrosine Phosphatases
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-akt
Quinazolines
Receptor Cross-Talk
Tyrphostins
