Cytochrome P450 2C9‐derived epoxyeicosatrienoic acids induce angiogenesis via cross‐talk with the epidermal growth factor receptor

Abstract

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.

CYP2C8 and CYP2C9 polymorphisms in relation to tumour characteristics and early breast cancer related events among 652 breast cancer patients

“…The degree of angiogenesis is not yet routinely evaluated in the clinical setting in Sweden, and we could, therefore, not evaluate whether there was any association between peritumoral vascular invasion and CYP2C8/9 haplotypes. It is plausible that we could have found an association, since CYP2C9-derived EETs stimulate angiogenesis (Michaelis et al, 2003). CYP2C9-derived EETs do so by a mechanism involving activation of the EGFR (Michaelis et al, 2003).…”

“…It is plausible that we could have found an association, since CYP2C9-derived EETs stimulate angiogenesis (Michaelis et al, 2003). CYP2C9-derived EETs do so by a mechanism involving activation of the EGFR (Michaelis et al, 2003). One study reported high expression of EGFR to be inversely correlated with nodal metastases and shorter, distant disease-free survival in a group of breast cancer patients who had received 2 years of adjuvant tamoxifen treatment (Dihge et al, 2008).…”

“…In vitro studies have shown that overexpression of CYP2C9 elicits angiogenesis via activation of the epidermal growth factor receptor (EGFR) (Michaelis et al, 2003). Jiang et al (2007) showed that CYP epoxygenase overexpression enhanced tumour metastasis of MDA-MB-231 human breast carcinoma cells to the lungs of athymic BALB/C mice.…”

Müller glia cells regulate Notch signaling and retinal angiogenesis via the generation of 19,20-dihydroxydocosapentaenoic acid

“…1 A), and although the EETs reported to induce angiogenesis in the chick chorioallantoic membrane (Michaelis et al, 2003) and the vascularization of Matrigel plugs implanted into wild-type mice Webler et al, 2008). Moreover, the overexpression of the human CYP2C11 and 2J2 enzymes in the ischemic rat hindlimb model was found to increase muscle capillary density (Wang et al, 2005).…”

“…The first link between CYP enzymes and angiogenesis was obtained in co-cultures of astrocytes and endothelial cells in which arachidonic acid epoxides (epoxyeicosatrienoic acids [EETs]) released from astrocytes increased endothelial cell proliferation and elicited the formation of capillary-like structures (Munzenmaier and Harder, 2000;Zhang and Harder, 2002). Also, the overexpression of the CYP2C9 epoxygenase in, and/or the application of 11,12-or 14,15-EET to monocultures of endothelial cells was associated with angiogenesis Michaelis et al, 2003). In vivo data rapidly followed to support these in vitro findings, with corresponding diols by the soluble epoxide hydrolase (sEH; gene = Ephx2; Konkel and Schunck, 2011;Imig, 2012).…”