ENDOTHELIN-1 IS A MEDIATOR OF INTIMAL HYPERPLASIA IN ORGAN-CULTURE OFHUMAN SAPHENOUS-VEIN

Background Endothelin-1 (ET-1) is a powerful vasoconstrictor and a pot ent mitogen for vascular smooth muscle cells. Excessive smooth muscle cell proliferation is a feature of intimal hyperplasia, the pathologic al lesion of vein graft stenosis. This study investigates the role of ET-1 in isolated human saphenous vein smooth muscle cells and also in an organ culture of the human saphenous vein. Methods Growth-arrested human saphenous vein smooth muscle cells were stimulated with ET-1 and proliferation quantified by [H-3]thymidine uptake in these cells comp ared with unstimulated control cells. Organ cultures of the human saph enous vein were established with endothelium intact, with endothelium denuded, and with endothelium denuded and the culture medium supplemen ted with ET-1. Results ET-1 stimulated DNA synthesis in isolated smoot h muscle cells in a dose-dependent manner with half-maximal stimulatio n at 1 nmol/l. Addition of ET-1 to denuded vein caused a significant i ncrease in median (range) neointimal thickness, from 4 (0-19) to 20 (4 -30) mu m (P < 0.05). In veins cultured with ET-I a parallel increase in median (range) neointimal proliferation index, from 21 (0-31) to 33 (23-46) per cent (P < 0.05), was also observed. Conclusion These resu lts demonstrate that ET-1 is a mediator of intimal hyperplasia in huma n saphenous vein in vitro. Endothelin receptor antagonists may therefo re be of therapeutic value in the modulation of vein graft intimal hyp erplasia.