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Am J Physiol Cell Physiol 294: C1215-C1226, 2008. First published March 26, 2008; doi:10.1152/ajpcell.00452.2007
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GROWTH, DIFFERENTIATION, AND APOPTOSIS

Thrombin mediates mitogenesis and survival of human endothelial cells through distinct mechanisms

Panagiota Zania, Matthew Papaconstantinou, Christodoulos S. Flordellis, Michael E. Maragoudakis, and Nikos E. Tsopanoglou

Department of Pharmacology, Medical School, University of Patras, Patras, Greece

Submitted 1 October 2007 ; accepted in final form 23 March 2008

Thrombin has been reported to play a pivotal role in the initiation of angiogenesis by indirectly regulating and organizing a network of angiogenic molecules. In addition, it has been proposed that thrombin can directly activate endothelial cell proliferation. However, in this report it was shown that thrombin is a poor growth factor for human endothelial cells, and its modest mitogenic activity is mediated indirectly by the release of heparin-binding epidermal growth factor, subsequent to proteinase-activated receptor 1 (PAR1) activation. On the other hand, it was demonstrated that thrombin is a potent anti-apoptotic factor for endothelial cells, pointing to a novel role of thrombin in vascular protection. Analysis by annexin V-propidium iodide double staining revealed that thrombin, specifically, promoted survival of serum-starved endothelial cells in a concentration-dependent manner. In contrast to its mitogenic effect, the anti-apoptotic effect of thrombin was largely independent of its catalytic activity and was mediated through interaction with {alpha}{nu}β3 and {alpha}5β1 integrins, whereas the involvement of PAR1 was limited. These results provide new insights in understanding the role of thrombin in endothelial cell signaling and vascular biology.

angiogenesis; apoptosis; proteinase-activated receptor 1; integrins


Address for reprint requests and other correspondence: N. E. Tsopanoglou, Dept. of Pharmacology, Medical School, Univ. of Patras, 26500 Patras, Greece (e-mail: ntsopan{at}med.upatras.gr)






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