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Blood, Vol. 95 No. 2 (January 15), 2000:
pp. 543-550
Domain 5 of high molecular weight kininogen (kininostatin)
down-regulates endothelial cell proliferation and migration and
inhibits angiogenesis
Robert W. Colman,
Bradford A. Jameson,
Yingzhang Lin,
Donald Johnson, and
Shaker A. Mousa
From the Sol Sherry Thrombosis Research Center, Temple University
School of Medicine, Philadelphia, PA; Center for Neurovirology,
MCP-Hahnemann Medical School, Philadelphia, PA; and Cardiovascular
Division, DuPont Pharmaceuticals, Wilmington, DE.
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 µM with an
IC50 (concentration to yield 50% inhibition) = 0.12
µM. A D5 peptide, G486-K502, showed an IC50 = 0.2
µM, but a 25-mer peptide from a D3 cell binding domain only inhibited migration 10% at 139 µM (IC50 > 50 µM). D6
exhibited weaker inhibitory activity (IC50 = 0.50
µM). D5 also potently inhibited endothelial cell proliferation with
an IC50 = 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
(IC50 = 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.
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