title: Response of bovine endothelial cells to FGF-2 and VEGF is dependent on their site of origin: Relevance to the regulation of angiogenesis.
abstract: Angiogenesis, the formation of new capillary blood vessels, occurs almost exclusively in the microcirculation. This process is controlled by the interaction between factors with positive and negative regulatory activity. In this study, we have compared the effect of two well described positive regulators, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2) on bovine adrenal cortex-derived microvascular endothelial (BME) and bovine aortic endothelial (BAE) cells. The parameters we assessed included (a) cellular reorganization and lumen formation following exposure of the apical cell surface to a three-dimensional collagen gel; (b) organization of the actin cytoskeleton; (c) expression of thrombospondin-1 (TSP-1), an endogenous negative regulator of angiogenesis; and (d) extracellular proteolytic activity mediated by the plasminogen activator (PA)/plasmin system. 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 induced dramatic reorganization of actin microfilaments in BME cells, with neither 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 cells, 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 BME and BAE cells, while VEGF induced uPA and tissue-type PA in BME cells with 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 specificity 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 complementary mechanisms which, when acting in concert, might account for the synergistic effect.
authors.affiliation: Dibit, Scientific Institute San Raffaele, University of Milan, Milan, Italy.
authors.forename: U
authors.initials: U
authors.lastname: Cavallaro
authors.forename: M
authors.initials: M
authors.lastname: Tenan
authors.forename: V
authors.initials: V
authors.lastname: Castelli
authors.forename: A
authors.initials: A
authors.lastname: Perilli
authors.forename: N
authors.initials: N
authors.lastname: Maggiano
authors.forename: E G
authors.initials: EG
authors.lastname: Van Meir
authors.forename: R
authors.initials: R
authors.lastname: Montesano
authors.forename: M R
authors.initials: MR
authors.lastname: Soria
authors.forename: M S
authors.initials: MS
authors.lastname: Pepper
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D002196:Capillaries / Q000166:cytology; D002417:Cattle; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen; D003599:Cytoskeleton / Q000648:ultrastructure; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D022001:Focal Adhesions / Q000648:ultrastructure; D008222:Lymphokines / Q000494:pharmacology*; D018919:Neovascularization, Physiologic; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis / Q000235:genetics; D010960:Plasminogen Activators / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D019700:Thrombospondin 1 / Q000096:biosynthesis / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D008222:Lymphokines; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D003094:Collagen; D010960:Plasminogen Activators