Objective-Micromolar concentrations of the proangiogenic metabolite deoxyribose-1-phosphate (dRP) were detected in platelet supernatants by mass spectrometry. In this study, we assessed whether the release of dRP by platelets stimulates endothelial cell migration and angiogenesis.Methods and Results-Protein-free supernatants from thrombin-stimulated platelets increased human umbilical vein endothelial cell migratory activity in transmigration and monolayer repair assays. This phenomenon was ablated by genetic silencing of dRP-generating uridine phosphorylase (UP) and thymidine phosphorylase (TP) or pharmacological inhibition of UP and restored by exogenous dRP. The stimulation of endothelial cell migration by platelet-derived dRP correlated with upregulation of integrin beta(3), which was induced in a reactive oxygen species-dependent manner, and was mediated by the activity of the integrin heterodimer alpha(v)beta(3). The physiological relevance of dRP release by platelets was confirmed in a chick chorioallantoic membrane assay, where the presence of this metabolite in platelet supernatants strongly induced capillary formation.Conclusion-Platelet-derived dRP stimulates endothelial cell migration by upregulating integrin beta(3) in a reactive oxygen species-dependent manner. As demonstrated by our in vivo experiments, this novel paracrine regulatory pathway is likely to play an important role in the stimulation of angiogenesis by platelets. (Arterioscler Thromb Vasc Biol. 2010;30:2631-2638.)
Paracrine Stimulation of Endothelial Cell Motility and Angiogenesis by Platelet-Derived Deoxyribose-1-Phosphate
Campanella, Michelangelo;
2010
Abstract
Objective-Micromolar concentrations of the proangiogenic metabolite deoxyribose-1-phosphate (dRP) were detected in platelet supernatants by mass spectrometry. In this study, we assessed whether the release of dRP by platelets stimulates endothelial cell migration and angiogenesis.Methods and Results-Protein-free supernatants from thrombin-stimulated platelets increased human umbilical vein endothelial cell migratory activity in transmigration and monolayer repair assays. This phenomenon was ablated by genetic silencing of dRP-generating uridine phosphorylase (UP) and thymidine phosphorylase (TP) or pharmacological inhibition of UP and restored by exogenous dRP. The stimulation of endothelial cell migration by platelet-derived dRP correlated with upregulation of integrin beta(3), which was induced in a reactive oxygen species-dependent manner, and was mediated by the activity of the integrin heterodimer alpha(v)beta(3). The physiological relevance of dRP release by platelets was confirmed in a chick chorioallantoic membrane assay, where the presence of this metabolite in platelet supernatants strongly induced capillary formation.Conclusion-Platelet-derived dRP stimulates endothelial cell migration by upregulating integrin beta(3) in a reactive oxygen species-dependent manner. As demonstrated by our in vivo experiments, this novel paracrine regulatory pathway is likely to play an important role in the stimulation of angiogenesis by platelets. (Arterioscler Thromb Vasc Biol. 2010;30:2631-2638.)Pubblicazioni consigliate
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