Antiproliferative effect of UTP on human arterial and venous smooth musclecells

We have investigated the hypothesis that responses associated with prolifer ation are regulated by extracellular nucleotides such as ATP and UTP in cul tured human vascular smooth muscle cells (VSMC) derived from internal mamma ry artery (IMA) and saphenous vein (SV). Platelet-derived growth factor (PD GF), ATP, and UTP each generated an increase in cytosolic free Ca2+ concent ration ([Ca2+](i)) in both IMA- and SV-derived cells in the absence of dete ctable inositol 1,4,5-trisphosphate production. ATP alone had no effect on [H-3] thymidine incorporation into DNA, but with a submaximal concentration of PDGF it raised [H-3] thymidine incorporation in SV- but not IMA- derive d cells. UTP alone also was without effect on [H-3] thymidine incorporation or cell number. However, in both SV- and IMA- derived cells, UTP reduced t he PDGF-stimulated [H-3] thymidine response and PDGF-stimulated cell prolif eration. This cannot be explained by an inhibitory effect on the p42/p44 mi togen-activated protein kinase (MAPK) cascade, since this response to PDGF was not attenuated by UTP. We conclude that, in human VSMC of both arterial and venous origin, UTP acts as an antiproliferative regulator.