Submitted on October 1, 2007
Accepted on March 23, 2008
Thrombin mediates mitogenesis and survival of human endothelial cells through distinct mechanisms
Panagiota Zania1, Matthew Papaconstantinou1, Christodoulos S Flordellis1, Michael E. Maragoudakis1, and Nikos E Tsopanoglou1*
1 Department of Pharmacology, University of Patras, Medical School, Patras, Greece
* To whom correspondence should be addressed. E-mail: ntsopan{at}med.upatras.gr.
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 activate directly 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 
v
3 and 51 integrins, while the involvement of PAR1 was limited. These results provide new insights in understanding the role of thrombin in endothelial cell signaling and vascular biology.
