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CLEC-2-dependent platelet subendothelial accumulation by flow disturbance contributes to atherogenesis in mice
Rationale: Platelets play an essential role in atherosclerosis, but the underlying mechanisms remain to be addressed. This study is to investigate the role of platelets in d-flow induced vascular inflammation and the underlying mechanism. Methods: We established a disturbed blood flow (d-flow) model...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8581433/ https://www.ncbi.nlm.nih.gov/pubmed/34815786 http://dx.doi.org/10.7150/thno.64601 |
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author | Tang, Chaojun Wang, Lei Sheng, Yulan Zheng, Zhong Xie, Zhanli Wu, Fan You, Tao Ren, Lijie Xia, Lijun Ruan, Changgeng Zhu, Li |
author_facet | Tang, Chaojun Wang, Lei Sheng, Yulan Zheng, Zhong Xie, Zhanli Wu, Fan You, Tao Ren, Lijie Xia, Lijun Ruan, Changgeng Zhu, Li |
author_sort | Tang, Chaojun |
collection | PubMed |
description | Rationale: Platelets play an essential role in atherosclerosis, but the underlying mechanisms remain to be addressed. This study is to investigate the role of platelets in d-flow induced vascular inflammation and the underlying mechanism. Methods: We established a disturbed blood flow (d-flow) model by partial carotid ligation (PCL) surgery using atherosclerosis-susceptible mice and wild-type mice to observe the d-flow induced platelet accumulation in the subendothelium or in the plaque by immunostaining or transmission electron microscopy. The mechanism of platelet subendothelial accumulation was further explored by specific gene knockout mice. Results: We observed presence of platelets in atherosclerotic plaques either in the atheroprone area of aortic arch or in carotid artery with d-flow using Ldlr(-/-) or ApoE(-/-) mice on high fat diet. Immunostaining showed the subendothelial accumulation of circulating platelets by d-flow in vivo. Transmission electron microscopy demonstrated the accumulation of platelets associated with monocytes in the subendothelial spaces. The subendothelial accumulation of platelet-monocyte/macrophage aggregates reached peak values at 2 days after PCL. In examining the molecules that may mediate the platelet entry, we found that deletion of platelet C-type lectin-like receptor 2 (CLEC-2) reduced the subendothelial accumulation of platelets and monocytes/macrophages by d-flow, and ameliorated plaque formation in Ldlr(-/-) mice on high fat diet. Supportively, CLEC-2 deficient platelets diminished their promoting effect on the migration of mouse monocyte/macrophage cell line RAW264.7. Moreover, monocyte podoplanin (PDPN), the only ligand of CLEC-2, was upregulated by d-flow, and the myeloid-specific PDPN deletion mitigated the subendothelial accumulation of platelets and monocytes/macrophages. Conclusions: Our results reveal a new CLEC-2-dependent platelet subendothelial accumulation in response to d-flow to regulate vascular inflammation. |
format | Online Article Text |
id | pubmed-8581433 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
spelling | pubmed-85814332021-11-22 CLEC-2-dependent platelet subendothelial accumulation by flow disturbance contributes to atherogenesis in mice Tang, Chaojun Wang, Lei Sheng, Yulan Zheng, Zhong Xie, Zhanli Wu, Fan You, Tao Ren, Lijie Xia, Lijun Ruan, Changgeng Zhu, Li Theranostics Research Paper Rationale: Platelets play an essential role in atherosclerosis, but the underlying mechanisms remain to be addressed. This study is to investigate the role of platelets in d-flow induced vascular inflammation and the underlying mechanism. Methods: We established a disturbed blood flow (d-flow) model by partial carotid ligation (PCL) surgery using atherosclerosis-susceptible mice and wild-type mice to observe the d-flow induced platelet accumulation in the subendothelium or in the plaque by immunostaining or transmission electron microscopy. The mechanism of platelet subendothelial accumulation was further explored by specific gene knockout mice. Results: We observed presence of platelets in atherosclerotic plaques either in the atheroprone area of aortic arch or in carotid artery with d-flow using Ldlr(-/-) or ApoE(-/-) mice on high fat diet. Immunostaining showed the subendothelial accumulation of circulating platelets by d-flow in vivo. Transmission electron microscopy demonstrated the accumulation of platelets associated with monocytes in the subendothelial spaces. The subendothelial accumulation of platelet-monocyte/macrophage aggregates reached peak values at 2 days after PCL. In examining the molecules that may mediate the platelet entry, we found that deletion of platelet C-type lectin-like receptor 2 (CLEC-2) reduced the subendothelial accumulation of platelets and monocytes/macrophages by d-flow, and ameliorated plaque formation in Ldlr(-/-) mice on high fat diet. Supportively, CLEC-2 deficient platelets diminished their promoting effect on the migration of mouse monocyte/macrophage cell line RAW264.7. Moreover, monocyte podoplanin (PDPN), the only ligand of CLEC-2, was upregulated by d-flow, and the myeloid-specific PDPN deletion mitigated the subendothelial accumulation of platelets and monocytes/macrophages. Conclusions: Our results reveal a new CLEC-2-dependent platelet subendothelial accumulation in response to d-flow to regulate vascular inflammation. Ivyspring International Publisher 2021-10-03 /pmc/articles/PMC8581433/ /pubmed/34815786 http://dx.doi.org/10.7150/thno.64601 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. |
spellingShingle | Research Paper Tang, Chaojun Wang, Lei Sheng, Yulan Zheng, Zhong Xie, Zhanli Wu, Fan You, Tao Ren, Lijie Xia, Lijun Ruan, Changgeng Zhu, Li CLEC-2-dependent platelet subendothelial accumulation by flow disturbance contributes to atherogenesis in mice |
title | CLEC-2-dependent platelet subendothelial accumulation by flow disturbance contributes to atherogenesis in mice |
title_full | CLEC-2-dependent platelet subendothelial accumulation by flow disturbance contributes to atherogenesis in mice |
title_fullStr | CLEC-2-dependent platelet subendothelial accumulation by flow disturbance contributes to atherogenesis in mice |
title_full_unstemmed | CLEC-2-dependent platelet subendothelial accumulation by flow disturbance contributes to atherogenesis in mice |
title_short | CLEC-2-dependent platelet subendothelial accumulation by flow disturbance contributes to atherogenesis in mice |
title_sort | clec-2-dependent platelet subendothelial accumulation by flow disturbance contributes to atherogenesis in mice |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8581433/ https://www.ncbi.nlm.nih.gov/pubmed/34815786 http://dx.doi.org/10.7150/thno.64601 |
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