Paracrine stimulation of endothelial cell motility and angiogenesis by platelet-derived deoxyribose-1-phosphate.
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.


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 β(3), which was induced in a reactive oxygen species-dependent manner, and was mediated by the activity of the integrin heterodimer α(v)β(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.


CONCLUSIONS
Platelet-derived dRP stimulates endothelial cell migration by upregulating integrin β(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.
Pula
Giordano
G
Department of Veterinary Basic Sciences, Royal Veterinary College, University of London, United Kingdom. gpula@rvc.ac.uk
Garonna
Elena
E
Dunn
Warwick B
WB
Hirano
Michio
M
Pizzorno
Giuseppe
G
Campanella
Michelangelo
M
Schwartz
Edward L
EL
El Kouni
Mahmoud H
MH
Wheeler-Jones
Caroline P D
CP
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008401:Gas Chromatography-Mass Spectrometry; D020868:Gene Silencing; D006801:Humans; D039564:Integrin alphaV / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D039661:Integrin beta3 / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D019899:Paracrine Communication / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012267:Ribosemonophosphates / Q000378:metabolism*; D013917:Thrombin / Q000378:metabolism; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014543:Uridine Phosphorylase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D004791:Enzyme Inhibitors; C061248:ITGB3 protein, human; D039564:Integrin alphaV; D039302:Integrin alphaVbeta3; D039661:Integrin beta3; D017382:Reactive Oxygen Species; D012267:Ribosemonophosphates; D014543:Uridine Phosphorylase; C543750:TYMP protein, human; D013939:Thymidine Phosphorylase; D013917:Thrombin