The VEGFs and FGF-2 stimulate angiogenesis. Pigment epithelium-derived factor (PEDF) and thrombospondin-1 (TSP-1) strongly inhibit angiogenesis. Human umbilical vein endothelial cells (HUVECs) expressed VEGF-A, -B, -C, the VEGF receptors R1, R2, and R3, PEDF, FGF-2, and TSP-1, but VEGF-D transcripts were barely detectable. Hypoxia reduced the transcript levels of VEGF-C and its cognate receptor, VEGF-R3. PEDF blocked the effect of CoCl(2) on these two factors. The expression of VEGF-A and -B as well as VEGF-R1 and VEGF-R2 remained unchanged after exposure to hypoxia, PEDF, or both. There was a marked reduction in TSP-1 transcripts in CoCl(2) treated cultures and PEDF blocked this reduction. PEDF induced a small increase in FGF-2 transcripts in HUVECs, but there was no change in FGF-2 expression in HUVECs exposed to hypoxia or hypoxia plus PEDF. PEDF may control neovascularization, in part, by restoring the negative effects of hypoxia on the expression of a potent angiogenesis inhibitor, TSP-1. PEDF may also modulate vascular leakage by maintaining the transcriptional levels of the vascular homeostasis factors, VEGF-C and VEGF-R3 in hypoxic conditions.