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      Domain 5 of high molecular weight kininogen (kininostatin) down-regulates endothelial cell proliferation and migration and inhibits angiogenesis.

      Allantois, blood supply, Amino Acid Sequence, Animals, Carrier Proteins, chemistry, Cell Division, drug effects, Cells, Cultured, Chemotaxis, Chick Embryo, Chorion, Endothelium, Vascular, cytology, physiology, Fibroblast Growth Factor 2, pharmacology, Humans, Kininogen, High-Molecular-Weight, Microfilament Proteins, Models, Molecular, Molecular Sequence Data, Mutagenesis, Neovascularization, Physiologic, Peptide Fragments, chemical synthesis, Peptides, Protein Conformation, Protozoan Proteins, Recombinant Proteins, Sequence Alignment, Sequence Deletion, Sequence Homology, Amino Acid, Surface Properties, Umbilical Veins

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          We have demonstrated that high molecular weight kininogen (HK) binds specifically on endothelial cells to domain 2/3 of the urokinase receptor (uPAR). Inhibition by vitronectin suggests that kallikrein-cleaved HK (HKa) is antiadhesive. Plasma kallikrein bound to HK cleaves prourokinase to urokinase, initiating cell-associated fibrinolysis. We postulated that HK cell binding domains would inhibit angiogenesis. We found that recombinant domain 5 (D5) inhibited endothelial cell migration toward vitronectin 85% at 0.27 microM with an IC(50) (concentration to yield 50% inhibition) = 0.12 microM. A D5 peptide, G486-K502, showed an IC(50) = 0.2 microM, but a 25-mer peptide from a D3 cell binding domain only inhibited migration 10% at 139 microM (IC(50) > 50 microM). D6 exhibited weaker inhibitory activity (IC(50) = 0.50 microM). D5 also potently inhibited endothelial cell proliferation with an IC(50) = 30 nM, while D3 and D6 were inactive. Using deletion mutants of D5, we localized the smallest region for full activity to H441-D474. To further map the active region, we created a molecular homology model of D5 and designed a series of peptides displaying surface loops. Peptide 440-455 was the most potent (IC(50) = 100 nM) in inhibiting proliferation but did not inhibit migration. D5 inhibited angiogenesis stimulated by fibroblast growth factor FGF2 (97%) in a chicken chorioallantoic membrane assay at 270 nM, and peptide 400-455 was also inhibitory (79%). HK D5 (for which we suggest the designation, "kininostatin") is a potent inhibitor of endothelial cell migration and proliferation in vitro and of angiogenesis in vivo. (Blood. 2000;95:543-550)

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