Two faces of high-molecular-weight kininogen (HK) in angiogenesis: bradykinin turns it on and cleaved HK (HKa) turns it off.

High-molecular-weight kininogen (HK) is a plasma protein that possesses multiple physiological functions. Originally identified as a precursor of bradykinin, a bioactive peptide that regulates many cardiovascular processes, it is now recognized that HK plays important roles in fibrinolysis, thrombosis, and inflammation. HK binds to endothelial cells where it can be cleaved by plasma kallikrein to release bradykinin (BK). The remaining portion of the molecule, cleaved HK, is designated cleaved high-molecular-weight kininogen or HKa. While BK has been intensively studied, the physiological implication of the generation of HKa is not clear. Recent studies have revealed that HKa inhibits angiogenesis while BK promotes angiogenesis. These findings represent novel functions of the kallikrein-kinin system that have not yet been fully appreciated. In this review, we will briefly discuss the recent progress in the studies of the molecular mechanisms that mediate the antiangiogenic effect of HKa and the proangiogenic activity of BK.