Abstract-We have recently shown that angiotensin II activation of insulin-like growth factor 1 receptor transcription is a critical requirement for angiotensin-stimulated vascular smooth muscle cell growth; therefore, we examined the signaling pathway involved. In rat aortic smooth muscle cells, the antioxidants N-acetyl-L-cysteine (5 mmol/L) and pyrrolidine dithiocarbamate (100 mol/L) completely inhibited angiotensin II-stimulated increases in IGF-1R mRNA and protein levels, suggesting the involvement of reactive oxygen species. Indeed, catalase abolished the Ang II-stimulated increase of IGF-1R protein expression, and accordingly, H 2 O 2 (0.2 mmol/L) or the oxidized products of linoleic acid, hydroperoxyoctadecadienoic acids (10 mol/L), increased IGF-1R mRNA levels at 3 hours by 74Ϯ20% and 107Ϯ22% and increased receptor number at 24 hours by 51Ϯ6.7% and 55Ϯ7.4%, respectively. The protein tyrosine kinase inhibitors genistein and tyrphostin A25 also blocked angiotensin II increases in IGF-1R mRNA and protein levels and blocked the ability of hydroperoxyoctadecadienoic acids and H 2 O 2 to increase IGF-1R expression, suggesting that oxidative stress may be an early event in the angiotensin II signaling cascade. Furthermore, calcium chelation inhibited the angiotensin II effect. Transient transfection assays revealed that a Ϫ2350/ϩ640 IGF-1R promoter/luciferase construct was fully responsive to angiotensin II stimulation (127Ϯ20% increase). Ten millimoles per liter hydroperoxyoctadecadienoic acids and 0.2 mmol/L H 2 O 2 increased luciferase activity by 79Ϯ8.5% and 63Ϯ12%, respectively, and 5 mmol/L N-acetyl-L-cysteine blocked the angiotensin II-induced upregulation of luciferase activity by 70%. These data suggest that angiotensin II stimulates IGF-1R gene transcription via calcium-dependent activation of protein tyrosine kinase activity that lies downstream from an oxidant stimulus. These findings provide key insights into the signaling mechanisms whereby angiotensin II exerts its growth-promoting effects on the vasculature.