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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on April 4, 2006; DOI: 10.1124/jpet.105.099069

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Received for publication November 30, 2005.
Revised March 31, 2006.
Accepted for publication March 31, 2006.

Blockade of angiogenesis by small molecule antagonists to protease-activated receptor-1 (PAR-1): Association with endothelial cell growth suppression and induction of apoptosis

Panagiota Zania 1, Sosanna Kritikou 2, Christodoulos S Flordellis 1, Michael E Maragoudakis 1, Nikos E Tsopanoglou 3*

1 University of Patras 2 Universirty of Patras 3 University of Patras, Medical School

* Address correspondence to: E-mail: ntsopan{at}med.upatras.gr

Abstract

Many studies support the notion that protease-activated receptor-1 (PAR-1) plays a pivotal role in angiogenesis. However, direct evidence and understanding the molecular mechanisms involved were limited, because PAR-1 specific antagonists have been developed only recently. In the present study we evaluated the effects of two well characterized PAR-1 antagonists, SCH79797 and RWJ56110, in the angiogenic cascade. These antagonists suppressed both the basic angiogenesis and that stimulated by thrombin in the chick chorioallantoic membrane model in vivo. PAR-1 antagonists also abrogated tube formation in the in vitro Matrigel system. These inhibitory effects were dose-dependent and well correlated with the inhibitory effects of SCH79797 and RWJ56110 on primary endothelial cell proliferation and on the initiation of apoptosis. PAR-1 blockage resulted in inhibition of endothelial cell growth by increasing the sub-Go/G1 fraction and reducing the percentage of cells in the S- phase. Consistent with this, PAR-1 antagonists reduced incorporation of [3H]-thymidine in endothelial cells and blocked the phosphorylation of extracellular signal- regulated kinases in a fashion depending specifically on PAR-1 activation. Analysis by Annexin V/propidium iodide staining and poly(ADP-ribose)polymerase cleavage revealed that PAR-1 blockage increased apoptotic cell death by a mechanism involving caspases. These results provide further evidence that PAR-1 is key receptor that mediates angiogenesis and suggest PAR-1 as target for developing anti-angiogenic agents with potential therapeutic application in cancer and other angiogenesis-related diseases.


Key words: Angiogenesis, PAR-1antagonists, antiangiogenic agents, anticancer agents, apoptosis, endothelial cell growth


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