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Thromb Haemost 2010; 104(05): 875-885
DOI: 10.1160/TH10-01-0017
Theme Issue Article
Schattauer GmbH

Mechanisms by which cleaved kininogen inhibits endothelial cell differentiation and signalling

Robert W. Colman
1   The Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
,
Yi Wu
1   The Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
,
Yuchuan Liu
1   The Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
› Author Affiliations
Further Information

Publication History

Received: 08 January 2010

Accepted after major revision: 02 May 2010

Publication Date:
24 November 2017 (online)

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Summary

We have shown that cleaved high-molecular-weight kininogen inhibits endoththelial cell tube and vacuole formation in a concentration-dependent manner and this correlates with its recognised anti-angiogenic activity. The antibody against the urokinase plasminogen activator receptor (uPAR) mimicked the inhibitory effect of cleaved kininogen (HKa) on apoptosis (HKa: 30% and uPAR antibody: 26%) and tube formation. In tumour angiogenesis, cancer cells release angiogenic stimulators, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), thus stimulating the transformation of endogenous pro-uPA to uPA. The proteolytic enzyme urokinase plasminogen activator (uPA) then binds to its receptor in a complex with its inhibitor PAI-1, which results in the internalisation of this complex, and activates extracellular signal-regulated kinase (ERK). Recycling of the uPAR regulates the migration of endothelial cells (ECs). ERK activation stimulates migration and proliferation and suppresses apoptosis of ECs. HKa disrupted the uPA-uPAR complex, inhibited ERK activation, and blocked the internalization of uPAR, eventually resulting in cell death and cell motility arrest. Both are critical steps in angiogenesis.

Keywords

Urokinase / receptor - tissue factor / factor VII - endothelial cells - contact phase - cytokines
 

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