VEGF induces ECM synthesis and fibroblast activity in human lung fibroblasts

Pulmonary vascular remodelling is a characteristic sign in different lung disorders. Vascular endothelial growth factor (VEGF) is a key mediator in vascular remodelling. The objective was to study the role of VEGF on fibroblast activity, such as extracellular matrix (ECM) synthesis, migration and proliferative capacity and to study if VEGF is affected in different lung disorders. Studies were performed in human lung fibroblasts (HFL-1) and primary distal fibroblasts cultures from control subjects, patients with COPD (GOLD IV) and patients with bronchiolitis obliterans syndrome (BOS). Lung fibroblasts were stimulated with TGF-b1. VEGF165 synthesis was measured in the cell culture medium. Changes in synthesis of the ECM proteins proteoglycans and procollagen I, proliferation rate and migration were analysed after stimulations with VEGF165 (1-10000 pg/ml). TGF-β1 significantly enhanced VEGF synthesis in all cell types. There were no differences in VEGF synthesis between fibroblasts from control subjects and COPD patients, whereas patients with BOS had a higher VEGF synthesis (p<0.05) and expression of VEGFR2 compared to controls (p<0.05). VEGF significantly increased synthesis of the ECM proteins biglycan (p<0.05), essential for cell migration, and perlecan (p<0.05), key ECM in vascular basement membrane. There were no significant effects on versican, decorin or procollagen I. VEGF also significantly increased proliferation rate (p<0.001) and migration capacity (p<0.01) after 48 h. In conclusion, VEGF is promoting specific ECM synthesis and fibroblast activation. VEGF may have a crucial role in the interplay between fibroblasts and other cells in vascular remodelling processes in the distal lung.