Epoxyeicosatrienoic acids, cell signaling and angiogenesis.

Epoxyeicosatrienoic acids (EETs) are generated from arachidonic acid by cytochrome P450 (CYP) epoxygenases the expression of which is determined by hemodynamic and pharmacological stimuli as well as by hypoxia. The activation of CYP epoxygenases in endothelial cells is an important step in the vasodilatation that has been attributed to the endothelium-derived hyperpolarizing factor. However, in addition to regulating vascular tone EETs modulate several signaling cascades and affect cell proliferation, cell migration and angiogenesis. These include the epidermal growth factor receptor, tyrosine kinases and phosphatases, mitogen-activated protein kinases, protein kinase A, cyclooxygenase-2 and several transcription factors. To-date however, the importance of EETs in vascular homeostasis has been largely underestimated because of the labile nature of the EET-forming enzymes in cell culture. This also means that the contribution of CYP-derived products in the vast majority of the experimental models based on cell culture systems to address topics related to vascular signaling/homeostasis and angiogenesis has been overlooked.