Direct demonstration of insulin-like growth factor-I-induced nitric oxide production by endothelial cells

Hirokazu Tsukahara, Dmitri V. Gordienko, Burkhard Tonshoff, Marie C. Gelato, Michael S. Goligorsky

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294 Citations (Scopus)


Several lines of evidence indicate that insulin-like growth factor-I (IGF- I) is a potent mediator of vasodilation. To elucidate the mechanism and site of action of IGF-I, we performed continuous monitoring of nitric oxide (NO) release from endothelial cells using a highly-sensitive amperometric NO- sensor. Two types of cultured cells were used: human umbilical vein endothelial cells and immortalized rat renal interlobar artery endothelial cells. In separate experiments, [Ca2+](i) changes in response to IGF-I were measured spectrofluorometrically in fura-2-loaded cells. Stimulation with IGF-I resulted in a rapid, dose-dependent increase in [NO] as detected by the NO-probe positioned 1 mm above the monolayers, followed by a sustained elevation lasting for at least five minutes. The effect of IGF-I was significantly suppressed by pretreatment with anti-IGF-I antibody, suggesting that it was specific for IGF-I. N(G)-nitro-L-arginine methyl ester, an inhibitor of NO synthesis, significantly blunted responses to IGF-I, but dexamethasone preincubation did not reduce the IGF-I-induced release of NO. These results indicate that the observed IGF-I-induced release of NO is a result of activation of the constitutive, rather than the inducible type of NO synthase in endothelial cells. Genistein, a tyrosine kinase inhibitor, resulted in a profound suppression of the IGF-I-induced release of NO. IGF-I did not affect [Ca2+](i) in either types of cells. Therefore, IGF-I- induced NO production by both types of endothelial cells is mediated via a tyrosine kinase-dependent mechanism. IGF-I may be an important regulator of vascular tone in vivo through NO release from the vascular endothelium, and may contribute to the regulation of renal blood flow under physiological and pathophysiological conditions.

Original languageEnglish
Pages (from-to)598-604
Number of pages7
JournalKidney International
Issue number2
Publication statusPublished - Feb 1994
Externally publishedYes

ASJC Scopus subject areas

  • Nephrology


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