Differential regulation of the fibroblast growth factor (FGF) family by alpha(2)-macroglobulin: evidence for selective modulation of FGF-2-induced angiogenesis
Ir. Asplin et al., Differential regulation of the fibroblast growth factor (FGF) family by alpha(2)-macroglobulin: evidence for selective modulation of FGF-2-induced angiogenesis, BLOOD, 97(11), 2001, pp. 3450-3457
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.