"A variety of angiogenesis inducers have been described (Table 2), which can be divided in three classes (129). The first class consists of the VEGF family and the angiopoietins, which specifically act on endothelial cells. The second class contains most direct-acting molecules, including several cytokines, chemokines (157) and angiogenic enzymes (30, 39), which activate a broad range of target cells besides endothelial cells. The prototype member of this group, FGF-2 was one of the first angiogenic peptides to be characterized. The third group of angiogenic molecules includes the indirect-acting factors, whose effect on angiogenesis results from the release of direct-acting factors from macrophages, endothelial or tumor cells. The most extensively studied are tumor necrosis factor-a (TNF-a) and transforming growth factor-b (TGF-b), which inhibit endothelial cell proliferation in vitro. In vivo, TGF-b induces angiogenesis and stimulates the expression of TNF-a, FGF-2, platelet derived growth factor (PDGF) and VEGF by attracted inflammatory cells (63, 185). TNF-a has been shown to increase the expression of VEGF and its receptors, interleukin-8 (IL-8) and FGF-2 by endothelial cells, thus explaining its angiogenic properties in vivo (87, 261)."