B189
Betastatin, a novel fragment of human fibrinogen, is a potent inhibitor of activated endothelial cells
Emilia Krajewska, Claire Lewis, Yung-Yi Chen, Simon Tazzyman, Carolyn Staton
University of Sheffield, Sheffield, UK
The angiogenic pathway involves the migration, proliferation and differentiation of endothelial cells to form new blood vessels. These processes are tightly regulated by the complex interaction of endothelial cells with local growth factors and constituents of the extracellular matrix (ECM). Hemostatic proteins also appear to regulate tumor angiogenesis and we recently showed that plasmin-cleavage of human fibrinogen results in the generation of a fragment with potent anti-angiogenic functions in vitro and cytotoxic effects on endothelial cells in tumor vessels – fibrinogen-E-fragment (FgnE). We now demonstrate that a novel, 20-amino acid peptide derived from the N-terminus of the β-chain of FgnE (which we have termed Betastatin) which markedly inhibits the ability of human endothelial cells to form tubules in response to multiple angiogenic growth factors: VEGF, FGF2, HGF and PDGF. Betastatin had no effect on EC proliferation or migration, and caused only a minimal reduction in EC viability in the presence of these stimuli. By contrast, it markedly inhibited the ability of activated EC to adhere to important constituents of the extracellular matrix like collagen IV, fibronectin and vitronectin. Furthermore, data also show that Betastatin interacts with EC, at least in part, by binding to αvβ3. Taken together, we have identified a new, anti-angiogenic peptide derived from human fibrinogen which blocks the adhesion of activated EC to the ECM, an essential step in the angiogenic pathway. This peptide may therefore have utility in the treatment of angiogenesis-related diseases like cancer.
