High molecular weight kininogen (HK) is a
plasma protein that is cleaved by
plasma kallikrein in the clinical settings of
sepsis and chronic inflammatory diseases such as
rheumatoid arthritis and
Crohn's disease. This proteolytic event results in a nonapeptide,
bradykinin (BK), and a
kinin-free derivative of HK, namely HKa. BK promotes angiogenesis by upregulation of bFGF through the B1 receptor or by stimulation of
VEGF formation via the B2 receptor.
Kininogen-deficient rats show diminished angiogenesis when neovascularization is stimulated. The formation of HKa results in exposure of domain 5 (D5). HKa or D5 inhibit endothelial cell migration and proliferation, both of which are needed for angiogenesis. In the chicken chorioallantoic membrane assay when neovascularization is stimulated by bFGF or
VEGF, HKa or D5 inhibit angiogenesis.
Monoclonal antibody C11C1, which prevents binding of HK to endothelial cells, also limits its conversion to BK thus downregulating angiogenesis. In vivo, mAb C11C1 inhibits
tumor angiogenesis in mice as well as in experimental inflammatory
arthritis and
inflammatory bowel disease in Lewis rats. In vitro HKa or D5 inhibits endothelial cell adhesion to
vitronectin and
fibrinogen, resulting in anokis and apoptosis. The HKa
receptor, uPAR, forms a signaling complex containing the
integrin alphavbeta3 or alpha5beta1,
caveolin,
Src kinase Yes,
focal adhesion kinase and paxcillin. HKa physically disrupts the complex by interfering with the binding of
vitronectin to uPAR. Both mAb C11C1 and D5 have potential applications for controlling unwanted angiogenesis in
inflammation and
cancer.