Transforming growth factor β induces vascular endothelial growth factor elaboration from pleural mesothelial cells in vivo and in vitro

Vascular endothelial growth factor (VEGF) increases vascular permeability and is important in pleural effusion formation. In studies using transforming growth factor beta (TGF-beta) to produce pleurodesis, we observed that although TGF-beta was more effective than talc or doxycycline, it induced transient production of large pleural effusions. We hypothesized that TGF-beta stimulates VEGF production in pleural tissues in vivo, and by mesothelial cells in vitro. New Zealand White rabbits (n = 33) were given TGF-beta(2) (1.7 or 5.0 mug), talc (400 mg/kg), doxycycline (10 mg/kg), or buffer intra-pleurally. Pleural fluid was collected at 24 h. Intrapleural injection of TGF-beta(2) induced a dose-dependent increase in VEGF production. The pleural fluid VEGF level was 2-fold higher in rabbits given 5.0 mug of TGF-beta(2) than in those given 1.7 mug of TGF-beta(2) and 3-fold higher than in those given buffer. VEGF levels were higher after the injection of TGF-beta(2) than after administration of talc or doxycycline. The pleural fluid VEGF correlated significantly with the volume of pleural effusions (r = 0.79, p < 0.00001). In vitro, TGF-beta(2) stimulated a dose-dependent increase In VEGF production from murine pleural mesothelial cells. At 4 and 24 h, TGF-beta(2), but not talc or doxycycline, induced a significant increase in VEGF, when compared with controls. The mesothelial cell VEGF production was significantly reduced by anti-TGF-beta antibody in the TGF-beta(2), talc, and control (buffer and medium) groups. In conclusion, mesothelial cells are an important source of VEGF. TGF-P increases the VEGF production by mesothelial cells in vivo and in vitro.