Endothelial cell-induced cytoglobin expression in vascular smooth muscle cells contributes to modulation of nitric oxide.

Cytoglobin is a widely expressed heme protein that binds oxygen, carbon monoxide and nitric oxide. Recent examination of cytoglobin in the vasculature indicates that it contributes to nitric oxide availability, which is central to normal blood vessel function through regulation of smooth muscle cell tone and physiological response. Given the potential implications of cytoglobin in vascular function, we examined how cytoglobin might be uniquely regulated in vascular smooth muscle cells. Our data demonstrate that endothelial cells can increase the expression of cytoglobin in vascular smooth muscle cells, and the induction of cytoglobin is cell contact-dependent. We show that Notch signaling is necessary for endothelial cell-induced cytoglobin expression and Notch2 and Notch3 are sufficient to drive its expression in aortic smooth muscle cells. We further reveal that in cytoglobin-depleted smooth muscle cells there is increased cellular nitric oxide. These data demonstrate that, in addition to being the main producer of vascular nitric oxide, endothelial cells facilitate the ability of smooth muscle cells to metabolize nitric oxide through upregulation of cytoglobin. Our results reveal a novel mechanism by which Notch signaling contributes to vascular function through regulation of a gene that controls nitric oxide levels.