Differential regulation of the fibroblast growth factor (FGF) family by α2-macroglobulin: evidence for selective modulation of FGF-2–induced angiogenesis

Abstract

The fibroblast growth factor (FGF) family has an important role in processes such as angiogenesis, wound healing, and development in which precise control of proteinase activity is important. The human plasma proteinase inhibitor α2-macroglobulin (α2M) regulates cellular growth by binding and modulating the activity of many cytokines and growth factors. These studies investigate the ability of native and activated α2M (α2M*) to bind to members of the FGF family. Both α2M and α2M* bind specifically and saturably to FGF-1, -2, -4, and -6, although the binding to α2M* is of significantly higher affinity. Neither α2M nor α2M* bind to FGF-5, -7, -9, or -10. FGF-2 was chosen for more extensive study in view of its important role in angiogenesis. It was demonstrated that FGF-2 binds to the previously identified TGF-β binding site. The α2M* inhibits FGF-2–dependent fetal bovine heart endothelial cell proliferation in a dose-dependent manner. Unexpectedly, α2M* does not affect FGF-2–induced vascular tubule formation on Matrigel basement membrane matrix or collagen gels. Further studies demonstrate that FGF-2 partitions between fluid-phase α2M* and solid-phase Matrigel or collagen. These studies suggest that the ability of α2M* to modulate the activity of FGF-2 is dependent on an interplay with extracellular matrix components.