Many failures of vascular reconstructions are due to thrombosis and restenosis and are often attributed to inadequate endothelial regeneration at the site of endothelial denudation. Vascular permeability factor (VPF) is a naturally occurring growth factor responsible for vessel permeability and microvascular angiogenesis. Here, we show that VPF stimulated rabbit endothelial cell proliferation in vitro at concentrations 100 ng/ml. However, VPF had no effect on smooth muscle cell proliferation at these concentrations up to 500 ng/ml. When VPF was administered for 4 weeks (120 micrograms, twice weekly, i.v.) following balloon angioplasty-induced endothelial denudation of rabbit carotid artery, there was a significant increase in the in vivo regeneration of endothelium compared to control (57.5 +/- 6.7% vs. 38.3 +/- 1.9%, P < 0.01). Moreover, 8 weeks of VPF administration resulted in 88.1 +/- 3.1% re-endothelialization compared to control (44.7 +/- 3.8%). Hence, VPF appears to be a specific mitogen for endothelial regeneration.