Document Detail


The effect of P2Y-mediated platelet activation on the release of VEGF and endostatin from platelets.
MedLine Citation:
PMID:  20063989     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Vascular endothelial growth factor (VEGF) and endostatin are key protein modulators of angiogenesis found within platelets. The platelet activation pathways that control angiogenic protein release are incompletely elucidated. The differential release of pro-angiogenic and anti-angiogenic proteins from the platelet has been demonstrated for proteinase activated receptors (PARs). Given the ability of tumors to secrete ADP and the availability of ADP receptor antagonists clinically, we determined the influence of adenosine diphosphate (ADP) and the ADP receptors, P2Y(1) and P2Y(12), on platelet release of the angiogenic stimulator protein, VEGF, and the angiogenic inhibitor protein, endostatin. Minimally altered whole blood (WB) and platelet rich plasma (PRP) from healthy volunteers was stimulated with ADP alone (12.5 uM), in combination with a P2Y(1) antagonist (MRS2179) or a P2Y(12) antagonist (cangrelor). VEGF and endostatin protein concentrations were assessed by an ELISA assay. We report that maximally stimulating concentrations of ADP significantly increased VEGF release from platelets in both PRP and WB by 36+/-12% 36+/-12% 54+/-18% 36 +/- 12% (p < 0.05) respectively as compared to control. Both P2Y(1) and P2Y(12) receptor antagonism inhibited this release. Conversely, endostatin levels did not change following ADP stimulation in PRP, while a 4.7% (p = 0.03) increase was observed in WB. As compared to thrombin receptor activation, ADP activation was a weaker stimulus for VEGF release. We found that activation of platelets by ADP results in an increase in soluble VEGF concentrations with minimal effects on endostatin concentrations, suggesting ADP release in the tumor microenvironment may be, on balance, proangiogenic. P2Y receptor antagonism abrogates ADP mediated proangiogenic protein release and thus may represent a potential pharmacologic strategy for regulating platelet mediated angiogenesis.
Authors:
Nadia M Bambace; Jamie E Levis; Chris E Holmes
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Platelets     Volume:  21     ISSN:  1369-1635     ISO Abbreviation:  Platelets     Publication Date:  2010  
Date Detail:
Created Date:  2010-02-12     Completed Date:  2010-05-10     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9208117     Medline TA:  Platelets     Country:  England    
Other Details:
Languages:  eng     Pagination:  85-93     Citation Subset:  IM    
Affiliation:
Department of Medicine, University of Vermont, Burlington, Vermont, USA.
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MeSH Terms
Descriptor/Qualifier:
Adenosine Diphosphate / metabolism,  pharmacology
Blood Platelets / drug effects,  metabolism*
Dose-Response Relationship, Drug
Endostatins / secretion*
Humans
Neoplasms / metabolism,  pathology
Neovascularization, Pathologic / metabolism
Platelet Activation / drug effects,  physiology*
Receptor, PAR-1 / agonists
Receptors, Purinergic P2 / antagonists & inhibitors,  metabolism*
Vascular Endothelial Growth Factor A / secretion*
Chemical
Reg. No./Substance:
0/Endostatins; 0/Receptor, PAR-1; 0/Receptors, Purinergic P2; 0/Vascular Endothelial Growth Factor A; 0/purinoceptor P2Y1; 0/purinoceptor P2Y12; 58-64-0/Adenosine Diphosphate

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