BACKGROUND Vascular endothelial growth factor (VEGF)/ vascular permeability factor (VPF) is an endothelial cell (EC) mitogen. This feature is considered central to the documented role of VEGF/VPF in promoting angiogenesis. More recent evidence suggests that VEGF/VPF may also serve a "maintenance" function, modulating various aspects of EC biology. In the present study, we sought to determine the extent to which VEGF/VPF may stimulate the release of NO from normal ECs. RESULTS VEGF/VPF produced a dose-dependent rise in NO concentration ([NO]) from vascular segments of rabbit thoracic aorta, pulmonary artery, and inferior vena cava. In comparison to stimulation with acetylcholine, the onset of increased [NO] after administration of VEGF/VPF was slower, reaching a maximum value after 8 minutes. Preincubation of the aortic segments with L-arginine raised by twofold both baseline [NO] and [NO] stimulated by addition of 2.5 micrograms/mL VEGF/VPF. Removal of CaCl2 from the Krebs solution, disruption of the endothelium, and administration of NG-monomethyl-L-arginine abrogated the stimulatory effect of 10 micrograms/mL VEGF/VPF. Similar findings were documented with an NO-specific polarographic electrode to measure NO released from cultured human umbilical vein ECs. CONCLUSIONS VEGF/VPF stimulates production of NO from rabbit and human ECs. This finding (1) constitutes inferential evidence for the presence of functional VEGF/VPF receptors on quiescent endothelium of the adult rabbit as well as human ECs and (2) supports the notion that putative maintenance functions of VEGF/VPF may include regulation of baseline synthesis and/or release of EC NO.