The proliferation of vascular cells contributes to the formation of neointima and hypertrophy of the blood vessel wall. Here we show that mechanical stretch possibly regulates the proliferation of vascular cells via the mediation of cell death in a rat vein graft model. The wall of vein grafts is subject to a suddenly increased mechanical stretch due to exposure to arterial blood pressure. Such a stretch induces rapid cell death with a reduction in cell density by approximately 60% within the first day after surgery. The initial cell death was followed by an increase in the percentage of proliferating cells, as shown by a BrdU incorporation assay (1.55 +/- 1.27%, 8.48 +/- 2.27%, 11.93 +/- 2.36%, 6.36 +/- 1.77%, and 5.60 +/- 1.46% at days 1, 5, 10, 20, and 30, respectively). When mechanical stretch was reduced by restraining the vein graft using a polytetrafluoroethylene sheath, the percentage of proliferating cells reduced significantly (0.76 +/- 0.76%, 1.70 +/- 0.46%, 1.29 +/- 0.56%, 0.99 +/- 0.83%, and 0.47+/-0.52% at days 1, 5, 10, 20, and 30, respectively). A further reduction in cell density, induced by local administration of a cell death inducer ceramide to experimental vein grafts (without sheath), enhanced subsequent cell proliferation. In contrast, a prevention of cell death, induced by local administration of a cell death inhibitor tetrapeptide-aldehyde DEVD-CHO to experimental vein grafts (without sheath), significantly reduced subsequent cell proliferation. These results suggest that mechanical stretch induces cell death, which possibly mediates subsequent cell proliferation in the present model.