Stabilizing Role of Platelet P2Y12 Receptors in Shear-Dependent Thrombus Formation on Ruptured Plaques
Background In most models of experimental thrombosis, healthy blood vessels are damaged. This results in the formation of a platelet thrombus that is stabilized by ADP signaling via P2Y12 receptors. However, such models do not predict involvement of P2Y12 in the clinically relevant situation of thro...
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| creator | Nergiz-Unal, Reyhan Cosemans, Judith M. E. M. Feijge, Marion A. H. van der Meijden, Paola E. J. Storey, Robert F. van Giezen, J. J. J. oude Egbrink, Mirjam G. A. Heemskerk, Johan W. M. Kuijpers, Marijke J. E. |
| description | Background In most models of experimental thrombosis, healthy blood vessels are damaged. This results in the formation of a platelet thrombus that is stabilized by ADP signaling via P2Y12 receptors. However, such models do not predict involvement of P2Y12 in the clinically relevant situation of thrombosis upon rupture of atherosclerotic plaques. We investigated the role of P2Y12 in thrombus formation on (collagen-containing) atherosclerotic plaques in vitro and in vivo, by using a novel mouse model of atherothrombosis. Methodology Plaques in the carotid arteries from Apoe−/− mice were acutely ruptured by ultrasound treatment, and the thrombotic process was monitored via intravital fluorescence microscopy. Thrombus formation in vitro was assessed in mouse and human blood perfused over collagen or plaque material under variable conditions of shear rate and coagulation. Effects of two reversible P2Y12 blockers, ticagrelor (AZD6140) and cangrelor (AR-C69931MX), were investigated. Principal Findings Acute plaque rupture by ultrasound treatment provoked rapid formation of non-occlusive thrombi, which were smaller in size and unstable in the presence of P2Y12 blockers. In vitro, when mouse or human blood was perfused over collagen or atherosclerotic plaque material, blockage or deficiency of P2Y12 reduced the thrombi and increased embolization events. These P2Y12 effects were present at shear rates >500 s−1, and they persisted in the presence of coagulation. P2Y12-dependent thrombus stabilization was accompanied by increased fibrin(ogen) binding. Conclusions/Significance Platelet P2Y12 receptors play a crucial role in the stabilization of thrombi formed on atherosclerotic plaques. This P2Y12 function is restricted to high shear flow conditions, and is preserved in the presence of coagulation. |
| doi_str_mv | 10.1371/journal.pone.0010130 |
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E. M. ; Feijge, Marion A. H. ; van der Meijden, Paola E. J. ; Storey, Robert F. ; van Giezen, J. J. J. ; oude Egbrink, Mirjam G. A. ; Heemskerk, Johan W. M. ; Kuijpers, Marijke J. E.</creator><contributor>Wang, Yu</contributor><creatorcontrib>Nergiz-Unal, Reyhan ; Cosemans, Judith M. E. M. ; Feijge, Marion A. H. ; van der Meijden, Paola E. J. ; Storey, Robert F. ; van Giezen, J. J. J. ; oude Egbrink, Mirjam G. A. ; Heemskerk, Johan W. M. ; Kuijpers, Marijke J. E. ; Wang, Yu</creatorcontrib><description>Background In most models of experimental thrombosis, healthy blood vessels are damaged. This results in the formation of a platelet thrombus that is stabilized by ADP signaling via P2Y12 receptors. However, such models do not predict involvement of P2Y12 in the clinically relevant situation of thrombosis upon rupture of atherosclerotic plaques. We investigated the role of P2Y12 in thrombus formation on (collagen-containing) atherosclerotic plaques in vitro and in vivo, by using a novel mouse model of atherothrombosis. Methodology Plaques in the carotid arteries from Apoe−/− mice were acutely ruptured by ultrasound treatment, and the thrombotic process was monitored via intravital fluorescence microscopy. Thrombus formation in vitro was assessed in mouse and human blood perfused over collagen or plaque material under variable conditions of shear rate and coagulation. Effects of two reversible P2Y12 blockers, ticagrelor (AZD6140) and cangrelor (AR-C69931MX), were investigated. Principal Findings Acute plaque rupture by ultrasound treatment provoked rapid formation of non-occlusive thrombi, which were smaller in size and unstable in the presence of P2Y12 blockers. In vitro, when mouse or human blood was perfused over collagen or atherosclerotic plaque material, blockage or deficiency of P2Y12 reduced the thrombi and increased embolization events. These P2Y12 effects were present at shear rates >500 s−1, and they persisted in the presence of coagulation. P2Y12-dependent thrombus stabilization was accompanied by increased fibrin(ogen) binding. Conclusions/Significance Platelet P2Y12 receptors play a crucial role in the stabilization of thrombi formed on atherosclerotic plaques. This P2Y12 function is restricted to high shear flow conditions, and is preserved in the presence of coagulation.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0010130</identifier><identifier>PMID: 20405028</identifier><language>eng</language><publisher>San Francisco: Public Library of Science</publisher><subject>Acute coronary syndromes ; Adenosine ; Adenosine diphosphate ; Animal models ; Apolipoprotein E ; Arteries ; Arteriosclerosis ; Atherosclerosis ; Biochemistry ; Blockage ; Blood ; Blood clots ; Blood platelets ; Blood vessels ; Cardiology ; Cardiovascular Disorders/Vascular Biology ; Carotid arteries ; Carotid artery ; Cell Biology/Cell Signaling ; Coagulation ; Collagen ; Embolization ; Fibrin ; Fluorescence ; Fluorescence microscopy ; Hematology ; In vivo methods and tests ; Pharmacology ; Physiology/Cardiovascular Physiology and Circulation ; Plaques ; Platelets ; Receptors ; Rodents ; Rupture ; Rupturing ; Shear flow ; Shear rate ; Signaling ; Stabilization ; Studies ; Thromboembolism ; Thrombosis ; Ultrasound ; Veins & arteries</subject><ispartof>PloS one, 2010-04, Vol.5 (4), p.e10130</ispartof><rights>2010 Nergiz-Unal et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Nergiz-Unal et al. 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c470t-cdec72863529e03bfc23f1e57471833dd1bff74966fad9b04679d8d74416ad803</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2853564/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2853564/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2928,23866,27924,27925,53791,53793</link.rule.ids></links><search><contributor>Wang, Yu</contributor><creatorcontrib>Nergiz-Unal, Reyhan</creatorcontrib><creatorcontrib>Cosemans, Judith M. E. M.</creatorcontrib><creatorcontrib>Feijge, Marion A. H.</creatorcontrib><creatorcontrib>van der Meijden, Paola E. J.</creatorcontrib><creatorcontrib>Storey, Robert F.</creatorcontrib><creatorcontrib>van Giezen, J. J. J.</creatorcontrib><creatorcontrib>oude Egbrink, Mirjam G. A.</creatorcontrib><creatorcontrib>Heemskerk, Johan W. M.</creatorcontrib><creatorcontrib>Kuijpers, Marijke J. E.</creatorcontrib><title>Stabilizing Role of Platelet P2Y12 Receptors in Shear-Dependent Thrombus Formation on Ruptured Plaques</title><title>PloS one</title><description>Background In most models of experimental thrombosis, healthy blood vessels are damaged. This results in the formation of a platelet thrombus that is stabilized by ADP signaling via P2Y12 receptors. However, such models do not predict involvement of P2Y12 in the clinically relevant situation of thrombosis upon rupture of atherosclerotic plaques. We investigated the role of P2Y12 in thrombus formation on (collagen-containing) atherosclerotic plaques in vitro and in vivo, by using a novel mouse model of atherothrombosis. Methodology Plaques in the carotid arteries from Apoe−/− mice were acutely ruptured by ultrasound treatment, and the thrombotic process was monitored via intravital fluorescence microscopy. Thrombus formation in vitro was assessed in mouse and human blood perfused over collagen or plaque material under variable conditions of shear rate and coagulation. Effects of two reversible P2Y12 blockers, ticagrelor (AZD6140) and cangrelor (AR-C69931MX), were investigated. Principal Findings Acute plaque rupture by ultrasound treatment provoked rapid formation of non-occlusive thrombi, which were smaller in size and unstable in the presence of P2Y12 blockers. In vitro, when mouse or human blood was perfused over collagen or atherosclerotic plaque material, blockage or deficiency of P2Y12 reduced the thrombi and increased embolization events. These P2Y12 effects were present at shear rates >500 s−1, and they persisted in the presence of coagulation. P2Y12-dependent thrombus stabilization was accompanied by increased fibrin(ogen) binding. Conclusions/Significance Platelet P2Y12 receptors play a crucial role in the stabilization of thrombi formed on atherosclerotic plaques. This P2Y12 function is restricted to high shear flow conditions, and is preserved in the presence of coagulation.</description><subject>Acute coronary syndromes</subject><subject>Adenosine</subject><subject>Adenosine diphosphate</subject><subject>Animal models</subject><subject>Apolipoprotein E</subject><subject>Arteries</subject><subject>Arteriosclerosis</subject><subject>Atherosclerosis</subject><subject>Biochemistry</subject><subject>Blockage</subject><subject>Blood</subject><subject>Blood clots</subject><subject>Blood platelets</subject><subject>Blood vessels</subject><subject>Cardiology</subject><subject>Cardiovascular Disorders/Vascular Biology</subject><subject>Carotid arteries</subject><subject>Carotid artery</subject><subject>Cell Biology/Cell Signaling</subject><subject>Coagulation</subject><subject>Collagen</subject><subject>Embolization</subject><subject>Fibrin</subject><subject>Fluorescence</subject><subject>Fluorescence microscopy</subject><subject>Hematology</subject><subject>In vivo methods and tests</subject><subject>Pharmacology</subject><subject>Physiology/Cardiovascular Physiology and Circulation</subject><subject>Plaques</subject><subject>Platelets</subject><subject>Receptors</subject><subject>Rodents</subject><subject>Rupture</subject><subject>Rupturing</subject><subject>Shear flow</subject><subject>Shear rate</subject><subject>Signaling</subject><subject>Stabilization</subject><subject>Studies</subject><subject>Thromboembolism</subject><subject>Thrombosis</subject><subject>Ultrasound</subject><subject>Veins & arteries</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp1kU1r3DAQhkVo6W7S_oNABT17oy9L9qVQNs0HLCRskkNOQrZGu168livJheTXx0uc0B4CAzMw7zzDzIvQKSULyhU92_khdKZd9L6DBSGUUE6O0JyWnGWSEf7pn3qGjmPcEZLzQsovaMaIIDlhxRy5u2Sqpm2em26D174F7B2-bU2CFhK-ZY-U4TXU0CcfIm46fLcFE7Jz6KGz0CV8vw1-Xw0RX_iwN6nxHR5jPfRpCGAPqD8DxK_oszNthG9TPkEPF7_vl1fZ6ubyevlrldVCkZTVFmrFCslzVgLhlasZdxRyJRQtOLeWVs4pUUrpjC0rIqQqbWGVEFQaWxB-gr6_cvvWRz29KGrKilLkPFd0VPycFEO1B1uPNwTT6j40exOetDeN_r_TNVu98X81K0aAFCPgxwQI_nBa-mCNeFXVwccYwL1voEQf_Hub0gf_9OQffwH7EJAs</recordid><startdate>20100412</startdate><enddate>20100412</enddate><creator>Nergiz-Unal, Reyhan</creator><creator>Cosemans, Judith M. 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E. M. ; Feijge, Marion A. H. ; van der Meijden, Paola E. J. ; Storey, Robert F. ; van Giezen, J. J. J. ; oude Egbrink, Mirjam G. A. ; Heemskerk, Johan W. M. ; Kuijpers, Marijke J. 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E. M.</au><au>Feijge, Marion A. H.</au><au>van der Meijden, Paola E. J.</au><au>Storey, Robert F.</au><au>van Giezen, J. J. J.</au><au>oude Egbrink, Mirjam G. A.</au><au>Heemskerk, Johan W. M.</au><au>Kuijpers, Marijke J. E.</au><au>Wang, Yu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Stabilizing Role of Platelet P2Y12 Receptors in Shear-Dependent Thrombus Formation on Ruptured Plaques</atitle><jtitle>PloS one</jtitle><date>2010-04-12</date><risdate>2010</risdate><volume>5</volume><issue>4</issue><spage>e10130</spage><pages>e10130-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Background In most models of experimental thrombosis, healthy blood vessels are damaged. This results in the formation of a platelet thrombus that is stabilized by ADP signaling via P2Y12 receptors. However, such models do not predict involvement of P2Y12 in the clinically relevant situation of thrombosis upon rupture of atherosclerotic plaques. We investigated the role of P2Y12 in thrombus formation on (collagen-containing) atherosclerotic plaques in vitro and in vivo, by using a novel mouse model of atherothrombosis. Methodology Plaques in the carotid arteries from Apoe−/− mice were acutely ruptured by ultrasound treatment, and the thrombotic process was monitored via intravital fluorescence microscopy. Thrombus formation in vitro was assessed in mouse and human blood perfused over collagen or plaque material under variable conditions of shear rate and coagulation. Effects of two reversible P2Y12 blockers, ticagrelor (AZD6140) and cangrelor (AR-C69931MX), were investigated. Principal Findings Acute plaque rupture by ultrasound treatment provoked rapid formation of non-occlusive thrombi, which were smaller in size and unstable in the presence of P2Y12 blockers. In vitro, when mouse or human blood was perfused over collagen or atherosclerotic plaque material, blockage or deficiency of P2Y12 reduced the thrombi and increased embolization events. These P2Y12 effects were present at shear rates >500 s−1, and they persisted in the presence of coagulation. P2Y12-dependent thrombus stabilization was accompanied by increased fibrin(ogen) binding. Conclusions/Significance Platelet P2Y12 receptors play a crucial role in the stabilization of thrombi formed on atherosclerotic plaques. This P2Y12 function is restricted to high shear flow conditions, and is preserved in the presence of coagulation.</abstract><cop>San Francisco</cop><pub>Public Library of Science</pub><pmid>20405028</pmid><doi>10.1371/journal.pone.0010130</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Acute coronary syndromes Adenosine Adenosine diphosphate Animal models Apolipoprotein E Arteries Arteriosclerosis Atherosclerosis Biochemistry Blockage Blood Blood clots Blood platelets Blood vessels Cardiology Cardiovascular Disorders/Vascular Biology Carotid arteries Carotid artery Cell Biology/Cell Signaling Coagulation Collagen Embolization Fibrin Fluorescence Fluorescence microscopy Hematology In vivo methods and tests Pharmacology Physiology/Cardiovascular Physiology and Circulation Plaques Platelets Receptors Rodents Rupture Rupturing Shear flow Shear rate Signaling Stabilization Studies Thromboembolism Thrombosis Ultrasound Veins & arteries |
| title | Stabilizing Role of Platelet P2Y12 Receptors in Shear-Dependent Thrombus Formation on Ruptured Plaques |
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