MODULATION OF ENDOTHELIAL-CELL PROLIFERATION, ADHESION, AND MOTILITY BY RECOMBINANT HEPARIN-BINDING DOMAIN AND SYNTHETIC PEPTIDES FROM THE TYPE-I REPEATS OF THROMBOSPONDIN

Thrombospondin is an inhibitor of angiogenesis that modulates endothel ial cell adhesion, proliferation, and motility. Synthetic peptides fro m the second type I repeat of human thrombospondin containing the cons ensus sequence -Trp-Ser-Pro-Trp- and a recombinant heparin binding fra gment from the amino-terminus of thrombospondin mimic several of the a ctivities of the intact protein. The peptides and heparin-binding doma in promote endothelial cell adhesion, inhibit endothelial cell chemota xis to basic fibroblast growth factor (bFGF), and inhibit mitogenesis and proliferation of aortic and corneal endothelial cells. The peptide s also inhibit heparin-dependent binding of bFGF to corneal endothelia l cells. The antiproliferative activities of the peptides correlate wi th their ability to bind to heparin and to inhibit bFGF binding to hep arin. Peptides containing amino acid substitutions that eliminate hepa rin-binding do not alter chemotaxis or proliferation of endothelial ce lls. Inhibition of proliferation by the peptide is time-dependent and reversible. Thus, the antiproliferative activities of the thrombospond in peptides and recombinant heparin-binding domain result at least in part from competition with heparin-dependent growth factors for bindin g to endothelial cell proteoglycans. These results suggest that both t he Trp-Ser-Xaa-Trp sequences in the type I repeats and the amino-termi nal domain play roles in the antiproliferative activity of thrombospon din. (C) 1993 Wiley-Liss, Inc.