PT - JOURNAL ARTICLE AU - Panagiota Zania AU - Despina Gourni AU - Alfred C. Aplin AU - Roberto F. Nicosia AU - Christodoulos S. Flordellis AU - Michael E. Maragoudakis AU - Nikos E. Tsopanoglou TI - Parstatin, the Cleaved Peptide on Proteinase-Activated Receptor 1 Activation, Is a Potent Inhibitor of Angiogenesis AID - 10.1124/jpet.108.145664 DP - 2009 Feb 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 378--389 VI - 328 IP - 2 4099 - http://jpet.aspetjournals.org/content/328/2/378.short 4100 - http://jpet.aspetjournals.org/content/328/2/378.full SO - J Pharmacol Exp Ther2009 Feb 01; 328 AB - The proteolytic activation by thrombin of the proteinase-activated receptor 1 unveils the tethered peptide ligand and cleaves a 41-amino acid peptide. In this report, we show that this peptide, which we have designated as “parstatin,” is a potent inhibitor of angiogenesis. Synthesized parstatin suppressed both the basic angiogenesis and that stimulated by basic fibroblast growth factor and vascular endothelial growth factor in the chick embryo model in vivo and in the rat aortic ring assay. Parstatin also abrogated endothelial cell migration and capillary-like network formation on the Matrigel and fibrin angiogenesis models in vitro. Treatment of endothelial cells with parstatin resulted in inhibition of cell growth by inhibiting the phosphorylation of extracellular signal-regulated kinases in a specific and reversible fashion and by promoting cell cycle arrest and apoptosis through a mechanism involving activation of caspases. We have shown that parstatin acts as a cell-penetrating peptide, exerting its biological effects intracellularly. The uptake into cells and the inhibitory activity were dependent on parstatin hydrophobic region. These results support the notion that parstatin may represent an important negative regulator of angiogenesis with possible therapeutic applications. U.S. Government work not protected by U.S. copyright