Both Angiotensin II and transforming growth factor beta-1 (TGF-beta1) are important mediators of vascular smooth muscle cell function and have been reported to mediate the balance between proliferation and apoptosis. Some crosstalk between Angiotensin II and TGF-beta1 in end-organ hypertension has been established. However, whether TGF-beta1 is able to mediate Angiotensin II-induced vascular cell damage remains unknown. Vascular smooth muscle cells were obtained from rat thoracic aorta and cultured in 10% foetal calf serum. In all experiments, medium was changed to a low-serum (0.4% foetal calf serum) or serum-free one with or without Angiotensin II. Apoptosis was assessed by DNA fragmentation, DNA synthesis was measured as bromo-deoxyuridine uptake. TGF-beta1 production was determined by Enzyme-linked Immunosorbent Assay (ELISA) from cell conditioned media, RT-PCR from cell lysates and confocal immunostaining of fixed cells. Angiotensin II induced apoptosis in the absence of DNA synthesis when coincubated at 1 microM. Neither the specific anti-TGF-beta1 monoclonal antibody (50 microg/ml) nor the novel activin-like kinase (ALK)-4/5/7 synthetic inhibitor SB-431542 (4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide) at 10 microM were able to inhibit this effect. Angiotensin II induced expression of TGF-beta1 without further secretion of this cytokine. This effect was not affected by incubation with the AT1 inhibitor irbesartan (10 microM). A pharmacological approach to TGF-beta1 inhibition would be unable to reverse the apoptotic effect of Angiotensin II on vascular smooth muscle cells.