Inhibition of endothelial cell tube formation by the low molecular weight heparin, tinzaparin, is mediated by tissue factor pathway inhibitor

Shaker A. Mousa; S. Mohamed

doi:10.1160/TH04-02-0069

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2004; 92(03): 627-633
DOI: 10.1160/TH04-02-0069

Endothelium and Vascular Development

Schattauer GmbH

Inhibition of endothelial cell tube formation by the low molecular weight heparin, tinzaparin, is mediated by tissue factor pathway inhibitor

Shaker A. Mousa

¹Albany College of Pharmacy and Pharmaceutical Research Institute at Albany College of Pharmacy, Albany, New York, USA

,

S. Mohamed

¹Albany College of Pharmacy and Pharmaceutical Research Institute at Albany College of Pharmacy, Albany, New York, USA

› Institutsangaben

Abstract

Summary

Heparin and low molecular weight heparins (LMWHs) have both antithrombotic and anti-angiogenic activities. The antiangiogenic activity of LMWH may be associated with the release of endothelial tissue factor pathway inhibitor (TFPI), an important endogenous inhibitor of tissue factor/Factor VIIa (TF/fVIIa).To evaluate the effects of LMWH, tinzaparin, and TFPI in a model of angiogenesis-mediated processes, we compared the effects of tinzaparin, and recombinant TFPI in inhibiting either basic fibroblast growth factor-2 (FGF2) or TF/fVIIainduced endothelial cell tube formation in human umbilical vein endothelial cells (HUVEC).Our results show that tinzaparin and recombinant TFPI both blocked endothelial tube formation induced by either FGF2 or TF/fVIIa, in a concentration-dependent manner. Endothelial tube formation was only marginally inhibited by a potent and specific anti-Factor Xa, recombinant tick anticoagulant protein (rTAP). A monoclonal anti-TFPI antibody reversed the inhibitory effects of either tinzaparin or recombinant-TFPI on HUVEC tube formation. Tinzaparin fractions in the range of 8,000 to 12,600 Da were most effective in stimulating the release of TFPI from HUVEC. These results suggest that the inhibitory effect of the LMWH tinzaparin on endothelial tube formation is associated with stimulation of the release of TFPI, but not to anti-Factor Xa activity.

Keywords

Low molecular weight heparin - tinzaparin - endothelial cell tube formation - tissue factor pathway inhibitor

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