Background Recent studies indicate that serotonin (5-HT) has a growth-promoting effect on several different cell types, including smooth muscle cells. After percutaneous transluminal coronary angioplasty, there is damage and denudation of vascular endothelial cells, which promotes platelet aggregation at the site of injury. Aggregating platelets release 5-HT; thus, a high concentration of the amine may be present at sites of endothelial damage, which may act as a mitogen to endothelial cells.Methods and Results The mitogenic effect of 5-HT was examined on canine and bovine aortic endothelial cells by (1) assessing the increase in (Hydrogen-3)thymidine incorporation into DNA and (2) assessing the increase in the absolute number of cells after stimulation with 5-HT. 5-HT at an added concentration of 200 to 1000 micromole/L in the media induced a significant increase in (Hydrogen-3)thymidine incorporation into endothelial cells and an increase in cell number. This effect was not observed with fibroblasts. As the concentrations of added 5-HT were decreased, the endothelial cells had to be stimulated with 5-HT for longer periods to induce the same degree of cellular proliferation. The precursors and metabolic breakdown products of 5-HT were inactive. The 5-HT-induced endothelial proliferation was reversed by 5-HT2receptor antagonists and pertussis toxin. These data suggest that the mitogenic effect of 5-HT on endothelial cells is mediated by the 5-HT2receptor, which is coupled to a G protein.Conclusions 5-HT is a mitogen for endothelial cells at concentrations likely to be present at sites of vascular injury. This effect is probably mediated via the 5-HT2receptor. The growth-promoting effects of 5-HT on endothelial cells may facilitate the healing of intima after vascular damage. (Circulation. 1994;90:1919-1926.)