Cellular pathology of atherosclerosis: smooth muscle cells promote adhesion of platelets to cocultured endothelial cells.

2.50
Hdl Handle:
http://hdl.handle.net/2436/20992
Title:
Cellular pathology of atherosclerosis: smooth muscle cells promote adhesion of platelets to cocultured endothelial cells.
Authors:
Tull, Samantha P.; Anderson, Stephen I.; Hughan, Sascha C.; Watson, Steve P.; Nash, Gerard B.; Rainger, G.E.
Abstract:
Although platelets do not ordinarily bind to endothelial cells (EC), pathological interactions between platelets and arterial EC may contribute to the propagation of atheroma. Previously, in an in vitro model of atherogenesis, where leukocyte adhesion to EC cocultured with smooth muscle cells was greatly enhanced, we also observed attachment of platelets to the EC layer. Developing this system to specifically model platelet adhesion, we show that EC cocultured with smooth muscle cells can bind platelets in a process that is dependent on EC activation by tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta1. Recapitulating the model using EC alone, we found that a combination of TGF-beta1 and TNF-alpha promoted high levels of platelet adhesion compared with either agent used in isolation. Platelet adhesion was inhibited by antibodies against GPIb-IX-V or alpha(IIb)beta3 integrin, indicating that both receptors are required for stable adhesion. Platelet activation during interaction with the EC was also essential, as treatment with prostacyclin or theophylline abolished stable adhesion. Confocal microscopy of the surface of EC activated with TNF-alpha and TGF-beta1 revealed an extensive matrix of von Willebrand factor that was able to support the adhesion of flowing platelets at wall shear rates below 400 s(-1). Thus, we have demonstrated a novel route of EC activation which is relevant to the atherosclerotic microenvironment. EC activated in this manner would therefore be capable of recruiting platelets in the low-shear environments that commonly exist at points of atheroma formation.
Citation:
Circulation Research, 2006, 98(1): 98-104
Publisher:
American Heart Association, Inc.
Journal:
Circulation Research
Issue Date:
2006
URI:
http://hdl.handle.net/2436/20992
DOI:
10.1161/01.RES.0000198386.69355.87
PubMed ID:
16322482
Additional Links:
http://circres.ahajournals.org/cgi/reprint/98/1/98
Type:
Article
Language:
en
ISSN:
1524-4571
Appears in Collections:
Diabetes, Physiology and Molecular Medicine Research Group

Full metadata record

DC FieldValue Language
dc.contributor.authorTull, Samantha P.-
dc.contributor.authorAnderson, Stephen I.-
dc.contributor.authorHughan, Sascha C.-
dc.contributor.authorWatson, Steve P.-
dc.contributor.authorNash, Gerard B.-
dc.contributor.authorRainger, G.E.-
dc.date.accessioned2008-03-18T11:18:26Z-
dc.date.available2008-03-18T11:18:26Z-
dc.date.issued2006-
dc.identifier.citationCirculation Research, 2006, 98(1): 98-104en
dc.identifier.issn1524-4571-
dc.identifier.pmid16322482-
dc.identifier.doi10.1161/01.RES.0000198386.69355.87-
dc.identifier.urihttp://hdl.handle.net/2436/20992-
dc.description.abstractAlthough platelets do not ordinarily bind to endothelial cells (EC), pathological interactions between platelets and arterial EC may contribute to the propagation of atheroma. Previously, in an in vitro model of atherogenesis, where leukocyte adhesion to EC cocultured with smooth muscle cells was greatly enhanced, we also observed attachment of platelets to the EC layer. Developing this system to specifically model platelet adhesion, we show that EC cocultured with smooth muscle cells can bind platelets in a process that is dependent on EC activation by tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta1. Recapitulating the model using EC alone, we found that a combination of TGF-beta1 and TNF-alpha promoted high levels of platelet adhesion compared with either agent used in isolation. Platelet adhesion was inhibited by antibodies against GPIb-IX-V or alpha(IIb)beta3 integrin, indicating that both receptors are required for stable adhesion. Platelet activation during interaction with the EC was also essential, as treatment with prostacyclin or theophylline abolished stable adhesion. Confocal microscopy of the surface of EC activated with TNF-alpha and TGF-beta1 revealed an extensive matrix of von Willebrand factor that was able to support the adhesion of flowing platelets at wall shear rates below 400 s(-1). Thus, we have demonstrated a novel route of EC activation which is relevant to the atherosclerotic microenvironment. EC activated in this manner would therefore be capable of recruiting platelets in the low-shear environments that commonly exist at points of atheroma formation.en
dc.language.isoenen
dc.publisherAmerican Heart Association, Inc.en
dc.relation.urlhttp://circres.ahajournals.org/cgi/reprint/98/1/98en
dc.subjectSmooth muscle cellsen
dc.subjecte Endothelial cellsen
dc.subjectcCocultureen
dc.subjectPlatelet Adhesivenessen
dc.subjectTransforming growth factor beta 1en
dc.subject.meshAtherosclerosisen
dc.subject.meshCells, Cultureden
dc.subject.meshCoculture Techniquesen
dc.subject.meshEndothelial Cellsen
dc.subject.meshHumansen
dc.subject.meshMuscle, Smooth, Vascularen
dc.subject.meshMyocytes, Smooth Muscleen
dc.subject.meshPlatelet Adhesivenessen
dc.subject.meshPlatelet Glycoprotein GPIIb-IIIa Complexen
dc.subject.meshPlatelet Glycoprotein GPIb-IX Complexen
dc.subject.meshTransforming Growth Factor betaen
dc.subject.meshTransforming Growth Factor beta1en
dc.subject.meshTumor Necrosis Factor-alphaen
dc.subject.meshvon Willebrand Factoren
dc.titleCellular pathology of atherosclerosis: smooth muscle cells promote adhesion of platelets to cocultured endothelial cells.en
dc.typeArticleen
dc.identifier.journalCirculation Researchen

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