Long Pentraxin 3/TSG-6 Interaction: A Biological Rheostat for Fibroblast Growth Factor 2–Mediated Angiogenesis

Objective—Angiogenesis is regulated by the balance between pro- and antiangiogenic factors and by extracellular matrix
protein interactions. Fibroblast growth factor 2 (FGF2) is a major proangiogenic inducer inhibited by the interaction with
the soluble pattern recognition receptor long pentraxin 3 (PTX3). PTX3 is locally coexpressed with its ligand tumor
necrosis factor-stimulated gene-6 (TSG-6), a secreted glycoprotein that cooperates with PTX3 in extracellular matrix
assembly. Here, we characterized the effect of TSG-6 on PTX3/FGF2 interaction and FGF2-mediated angiogenesis.
Methods and Results—Solid phase binding and surface plasmon resonance assays show that TSG-6 and FGF2 bind the
PTX3 N-terminal domain with similar affinity. Accordingly, TSG-6 prevents FGF2/PTX3 interaction and suppresses the
inhibition exerted by PTX3 on heparan sulfate proteoglycan/FGF2/FGF receptor complex formation and on
FGF2-dependent angiogenesis in vitro and in vivo. Also, endogenous PTX3 exerts an inhibitory effect on vascularization
induced by FGF2 in a murine subcutaneous Matrigel plug assay, the inhibition being abolished in Ptx3-null mice
or by TSG-6 treatment in wild-type animals.
Conclusion—TSG-6 reverts the inhibitory effects exerted by PTX3 on FGF2-mediated angiogenesis through competition
of FGF2/PTX3 interaction. This may provide a novel mechanism to control angiogenesis in those pathological settings
characterized by the coexpression of TSG-6 and PTX3, in which the relative levels of these proteins may fine-tune the
angiogenic activity of FGF2.