ANG II potentiates mitogenic effect of norepinephrine in vascular muscle cells: role of FGF-2

We examined the possible cooperation between norepinephrine (NE) and ANG II on proliferation of cultured vascular smooth muscle cells (VSMCs) and the involved cellular mechanisms. Nanomolar NE concentrations stimulated VSMC proliferation through a prazosin-sensitive effect. The pretreatment of cells with 100 nM ANG II for 24 h significantly potentiated the NE-induced VSMC proliferation; this potentiating effect of ANG II was blocked by losartan but was unaffected by the AT(2) receptor antagonist PD-123177. ANG II pretreatment also potentiated the increase in inositol phosphate turnover and upregulated the cell expression of fibroblast growth factor (FGF-2) induced by NE. Anti-FGF-2 neutralizing antibodies prevented the potentiating effect of ANG II on NE-induced cell growth. Both ANG II and NE stimulated extracellular signal-related kinase (ERK1) activation, but an ANG II potentiation of the effect of NE on ERK1 activity was not detectable. Moreover, ANG II significantly increased protein synthesis but did not potentiate the hypertrophic effect of NE. These findings demonstrate that ANG II and NE cooperate in promoting VSMC growth and that FGF-2 upregulation is involved in this effect.