Dual effects of insulin-like growth factor-I on the constitutive and inducible nitric oxide (NO) synthase-dependent formation of NO in vascular cells

Abstract

The free radical nitric oxide (NO) has emerged as an important signal effector molecule that controls critical functions in the mammalian cardiovascular system in both healthy and diseased states. In normal blood vessels, NO is synthesized from L-arginine by a constitutively expressed NO synthase (NOS III) in endothelial cells. The endothelial formation of NO can be increased by both pharmacological and physiological agonists (e.g. bradykinin) and this effect is dependent on the interaction of calcium/calmodulin with NOS III. Recent observations suggest that NO is a pivotal mediator of insulin-like growth factor (IGF)-I-induced vasodilatation in humans and experimental animals. Administration of IGF-I in the human brachial artery increased blood flow in the forearm, an effect which was abolished by N(G)-monomethyl-L-arginine (L-NMMA), an inhibitor of NOS. Inhibitors of NOS also prevented the IGF-I-induced renal vasodilatation in anesthetized rats and in in vitro blood-perfused preparations of rat juxtamedullary nephrons. In addition, IGF-I caused concentration-dependent relaxation of precontracted isolated arteries that required the presence of a functional endothelium, and this effect was abolished by L-NMMA. Moreover, the rapid formation of NO in response to IGF-I is detected in cultured endothelial cells by an amperometric NO sensor. The signalling of NO formation is independent of changes in intracellular Ca2+ and involves tyrosine kinase and phosphatidylinositol-3-kinase. At sites of vascular injury, proinflammatory mediators can stimulate the expression of an inducible NOS (NOS II) that generates large amounts of NO for prolonged periods of time. IGF-I has been shown to inhibit the interleukin-1beta-induced formation of NO in cultured vascular smooth muscle cells by preventing the induction of NOS II. In conclusion, IGF-I may be an important regulator of vascular tone in part by modulating the formation of NO by NOS III and NOS II in the vascular wall.