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 processes such as angiogenesis, wound healing, and development in which precise control of proteinase activity is important. The human plasma proteinase inhibitor alpha(2)-macroglobulin (alpha(2)M) regulates cellular growth by binding and modulating the activity of many cytokines and growth factors. These studies investigate the ability of native and activated alpha(2)M (alpha(2)M*) to bind to members of the FGF family. Both alpha(2)M and alpha(2)M* bind specifically and saturably to FGF-1, -2, -4, and -6, although the binding to alpha(2)M* is of significantly higher affinity. Neither alpha(2)M nor alpha(2)M* 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-beta binding site. The alpha(2)M* inhibits FGF-2-dependent fetal bovine heart endothelial cell proliferation in a dose-dependent manner. Unexpectedly, alpha(2)M* 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 alpha(2)M* and solid-phase Matrigel or collagen. These studies suggest that the ability of alpha(2)M* to modulate the activity of FGF-2 is dependent on an interplay with extracellular matrix components. (Blood. 2001;97:3450-3457)
Asplin
I R
IR
Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
Wu
S M
SM
Mathew
S
S
Bhattacharjee
G
G
Pizzo
S V
SV
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D003094:Collagen; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007797:Laminin; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011509:Proteoglycans; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000511:alpha-Macroglobulins / Q000378:metabolism / Q000494:pharmacology*
D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D016212:Transforming Growth Factor beta; D000511:alpha-Macroglobulins; D016222:Fibroblast Growth Factor 2; C059485:matrigel; D003094:Collagen