Co-operation between endothelin and nitric oxide in promoting endothelial cell migration and angiogenesis

1, Among the diverse functions of endothelins (ET), their role in the remod elling of blood vessels remains poorly examined. In the present review, we summarize findings obtained in our laboratory and present four independent lines of evidence to support this novel function, We also demonstrate that the motogenic and angiogenic effects of ET are mediated via the ETB recepto r and that the functional endothelial nitric oxide synthase (NOS) is requis ite for this action. 2, We demonstrated that ET stimulates transmigration of endothelial cells i n a modified Boyden chamber and accelerates endothelial wound healing actin g via ETB receptors, 3. In genetically engineered Chinese hamster ovary cells expressing either ETB receptor or endothelial NOS or both, application of ET results in accel erated cell migration only when the receptor and the enzyme are coexpressed , Application of antisense oligonucleotides producing a specific knockdown of the endothelial NOS results in the loss of ET ability to stimulate endot helial cell migration in response to ET. 4, Finally, using a novel model of in vivo angiogenesis, we were able to de monstrate that ET enhances formation of new vessels, but this effect requir es functional endothelial NOS. 5, The described phenomenon of NO production, serving as a prerequisite for endothelial cell locomotion in response to activation of ETB receptor may explain a host of pathophysiological observations on inadequate angiogenesi s despite enhanced generation of ET-1. 6, Based on the contribution of endothelial cell migration to angiogenesis, these data may implicate insufficient NO production in pathological states (e,g, atherosclerosis, heart failure and hypertension) in the inappropriat e response to angiogenic stimuli.