Endothelin-1 is a mediator of intimal hyperplasia in organ culture of human saphenous vein

Abstract

Endothelin-1 (ET-1) is a powerful vasoconstrictor and a potent mitogen for vascular smooth muscle cells. Excessive smooth muscle cell proliferation is a feature of intimal hyperplasia, the pathological 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. Growth-arrested human saphenous vein smooth muscle cells were stimulated with ET-1 and proliferation quantified by [3H]thymidine uptake in these cells compared with unstimulated control cells. Organ cultures of the human saphenous vein were established with endothelium intact, with endothelium denuded, and with endothelium denuded and the culture medium supplemented with ET-1. ET-1 stimulated DNA synthesis in isolated smooth muscle cells in a dose-dependent manner with half-maximal stimulation at 1 nmol/l. Addition of ET-1 to denuded vein caused a significant increase in median (range) neointimal thickness, from 4 (0-19) to 20 (4-30) microns (P < 0.05). In veins cultured with ET-1 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. These results demonstrate that ET-1 is a mediator of intimal hyperplasia in human saphenous vein in vitro. Endothelin receptor antagonists may therefore be of therapeutic value in the modulation of vein graft intimal hyperplasia.