Response of bovine endothelial cells to FGF-2 and VEGF is dependent on their site of origin: Relevance to the regulation of angiogenesis

Angiogenesis, the formation of new capillary blood vessels, occurs almost e xclusively in the microcirculation. This process is controlled by the inter action between factors with positive and negative regulatory activity. In t his study, we have compared the effect of two well described positive regul ators, vascular endothelial growth factor (VEGF) and basic fibroblast growt h factor (FGF-2) on bovine adrenal cortex-derived microvascular endothelial (BME) and bovine aortic endothelial (BAE) cells. The parameters we assesse d included (a) cellular reorganization and lumen formation following exposu re of the apical cell surface to a three-dimensional collagen gel; (b) orga nization of the actin cytoskeleton; (c) expression of thrombospondin-1 (TSP -1), an endogenous negative regulator of angiogenesis; and (d) extracellula r proteolytic activity mediated by the plasminogen activator (PA)/plasmin s ystem. We found that (a) collagen gel overlay induces rapid reorganization and lumen formation in BME but not BAE cells; (b) FGF-2 but not VEGF induce d dramatic reorganization of actin microfilaments in BME cells, with neithe r cytokine affecting BAE cells; (c) FGF-2 decreased TSP-1 protein and mRNA expression in BME cells, an effect which was specific for FGF-2 and BME cel ls, since TSP-1 protein levels were unaffected by VEGF in BME cells, or by FGF-2 or VEGF in BAE cells; (d) FGF-2 induced urokinase-type PA (uPA) in BM E and BAE cells, while VEGF induced uPA and tissue-type PA in BME cells wit h no effect on BAE cells. Taken together, these findings reveal endothelial cell-type specific responses to FGF-2 and VEGF, and point to the greater s pecificity of these cytokines for endothelial cells of the microvasculature than for large vessel (aortic) endothelial cells. Furthermore, when viewed in the context of our previous observation on the synergistic interaction between VEGF and FGF-2, our present findings provide evidence for complemen tary mechanisms which, when acting in concert, might account for the synerg istic effect. (C) 2001 Wiley-Liss, Inc.