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Cyclic Stretch Enhances the Expression and Activity of Coronary Endothelium-Derived Hyperpolarizing Factor Synthase

Endothelium-derived hyperpolarizing factor (EDHF) mediates NO/prostacyclin-independent relaxation in the coronary circulation. Because hemodynamic stimuli modulate endothelial gene expression and because coronary arteries are subjected to pronounced variations in vessel distension, we determined the effects of cyclic stretch on the expression and activity of the coronary EDHF synthase/cytochrome P450 (CYP) 2C8/9. In cultured porcine coronary and human umbilical vein endothelial cells, acute application of cyclic stretch (6%, 1 Hz, 10 minutes) elicited the generation of 8,9-epoxyeicosatrienoic acid (EET), 11,12-EET, and 14,15-EET. Prolonged stretch (4 to 36 hours) increased the expression of CYP 2C mRNA and protein 5- to 10-fold and was accompanied by a 4- to 8-fold increase in EET generation. A corresponding increase in CYP 2C mRNA and protein was also observed in pressurized segments of porcine coronary artery perfused under pulsatile conditions (8%, 1 Hz) for 6 hours. Although in cultured endothelial cells, cyclic stretch elicited the rapid activation of tyrosine kinases as well as Akt and the p38 mitogen-activated protein kinase, the mechanism by which cyclic stretch induces the expression of CYP 2C could not be elucidated, because inhibitors of these pathways induced CYP 2C expression in cells maintained under static conditions. These results have identified coronary EDHF synthase/CYP 2C as a novel mechanosensitive gene product in native and cultured endothelial cells. Because this enzyme generates both EETs and superoxide anions, this finding has wide-reaching implications for vascular homeostasis in conditions of manifest endothelial dysfunction.