Differential regulation of the fibroblast growth factor (FGF) family by alpha(2)-macroglobulin: evidence for selective modulation of FGF-2-induced angiogenesis

The fibroblast growth factor (FGF) family has an important role in processe s such as angiogenesis, wound healing, and development in which precise con trol of proteinase activity is important. The human plasma proteinase inhib itor alpha (2)-macroglobulin (alpha M-2) regulates cellular growth by bindi ng and modulating the activity of many cytokines and growth factors. These studies investigate the ability of native and activated alpha Rn-2 (alpha M -2*) to bind to members of the FGF family. Both alpha M-2 and alpha M-2* bi nd specifically and saturably to FGF-1, -2,-4, and -6, although the binding to alpha M-2* is of significantly higher affinity. Neither alpha M-2 nor a lpha M-2* bind to FGF5, -7, -9, or -10. FGF-2 was chosen for more extensive study in view of its important role in angiogenesis. It was demonstrated t hat FGF-2 binds to the previously identified TGF-beta binding site. The alp ha M-2* inhibits FGF-2-dependent fetal bovine heart endothelial cell prolif eration in a dose-dependent manner. Unexpectedly, alpha M-2* does not affec t FGF-2-induced Vascular tubule formation on Matrigel basement membrane mat rix or collagen gels, Further studies demonstrate that FGF-2 partitions bet ween fluid-phase alpha M-2* and solid-phase Matrigel or collagen. These stu dies suggest that the ability of alpha M-2* to modulate the activity of FGF -2 is dependent on an interplay with extracellular matrix components. (Bloo d, 2001;97:3450-3457) (C) 2001 by The American Society of Hematology.