Cargando…
Serum‐Derived Small Extracellular Vesicles From Diabetic Mice Impair Angiogenic Property of Microvascular Endothelial Cells: Role of EZH2
BACKGROUND: Impaired angiogenic abilities of the microvascular endothelial cell (MVEC) play a crucial role in diabetes mellitus–impaired ischemic tissue repair. However, the underlying mechanisms of diabetes mellitus–impaired MVEC function remain unclear. We studied the role of serum‐derived small e...
Autores principales: | , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200714/ https://www.ncbi.nlm.nih.gov/pubmed/33988033 http://dx.doi.org/10.1161/JAHA.120.019755 |
_version_ | 1783707665243832320 |
---|---|
author | Cheng, Zhongjian Naga Srikanth Garikipati, Venkata Truongcao, May M. Cimini, Maria Huang, Grace Wang, Chunlin Benedict, Cindy Gonzalez, Carolina Mallaredy, Vandana Goukassian, David A. Verma, Suresh K. Kishore, Raj |
author_facet | Cheng, Zhongjian Naga Srikanth Garikipati, Venkata Truongcao, May M. Cimini, Maria Huang, Grace Wang, Chunlin Benedict, Cindy Gonzalez, Carolina Mallaredy, Vandana Goukassian, David A. Verma, Suresh K. Kishore, Raj |
author_sort | Cheng, Zhongjian |
collection | PubMed |
description | BACKGROUND: Impaired angiogenic abilities of the microvascular endothelial cell (MVEC) play a crucial role in diabetes mellitus–impaired ischemic tissue repair. However, the underlying mechanisms of diabetes mellitus–impaired MVEC function remain unclear. We studied the role of serum‐derived small extracellular vesicles (ssEVs) in diabetes mellitus–impaired MVEC function. METHODS AND RESULTS: ssEVs were isolated from 8‐week‐old male db/db and db/+ mice by ultracentrifugation and size/number were determined by the Nano‐sight tracking system. Diabetic ssEVs significantly impaired tube formation and migration abilities of human MVECs. Furthermore, local transplantation of diabetic ssEVs strikingly reduced blood perfusion and capillary/arteriole density in ischemic hind limb of wildtype C57BL/6J mice. Diabetic ssEVs decreased secretion/expression of several pro‐angiogenic factors in human MVECs. Mechanistically, expression of enhancer of zest homolog 2 (EZH2), the major methyltransferase responsible for catalyzing H3K27me3 (a transcription repressive maker), and H3K27me3 was increased in MVECs from db/db mice. Diabetic ssEVs increased EZH2 and H3K27me3 expression/activity in human MVECs. Expression of EZH2 mRNA was increased in diabetic ssEVs. EZH2‐specific inhibitor significantly reversed diabetic ssEVs‐enhanced expression of EZH2 and H3K27me3, impaired expression of angiogenic factors, and improved blood perfusion and vessel density in ischemic hind limb of C57BL/6J mice. Finally, EZH2 inactivation repressed diabetic ssEVs‐induced H3K27me3 expression at promoter of pro‐angiogenic genes. CONCLUSIONS: Diabetic ssEVs impair the angiogenic property of MVECs via, at least partially, transferring EZH2 mRNA to MVECs, thus inducing the epigenetic mechanism involving EZH2‐enhanced expression of H3K27me3 and consequent silencing of pro‐angiogenic genes. Our findings unravel the cellular mechanism and expand the scope of bloodborne substances that impair MVEC function in diabetes mellitus. |
format | Online Article Text |
id | pubmed-8200714 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82007142021-06-15 Serum‐Derived Small Extracellular Vesicles From Diabetic Mice Impair Angiogenic Property of Microvascular Endothelial Cells: Role of EZH2 Cheng, Zhongjian Naga Srikanth Garikipati, Venkata Truongcao, May M. Cimini, Maria Huang, Grace Wang, Chunlin Benedict, Cindy Gonzalez, Carolina Mallaredy, Vandana Goukassian, David A. Verma, Suresh K. Kishore, Raj J Am Heart Assoc Original Research BACKGROUND: Impaired angiogenic abilities of the microvascular endothelial cell (MVEC) play a crucial role in diabetes mellitus–impaired ischemic tissue repair. However, the underlying mechanisms of diabetes mellitus–impaired MVEC function remain unclear. We studied the role of serum‐derived small extracellular vesicles (ssEVs) in diabetes mellitus–impaired MVEC function. METHODS AND RESULTS: ssEVs were isolated from 8‐week‐old male db/db and db/+ mice by ultracentrifugation and size/number were determined by the Nano‐sight tracking system. Diabetic ssEVs significantly impaired tube formation and migration abilities of human MVECs. Furthermore, local transplantation of diabetic ssEVs strikingly reduced blood perfusion and capillary/arteriole density in ischemic hind limb of wildtype C57BL/6J mice. Diabetic ssEVs decreased secretion/expression of several pro‐angiogenic factors in human MVECs. Mechanistically, expression of enhancer of zest homolog 2 (EZH2), the major methyltransferase responsible for catalyzing H3K27me3 (a transcription repressive maker), and H3K27me3 was increased in MVECs from db/db mice. Diabetic ssEVs increased EZH2 and H3K27me3 expression/activity in human MVECs. Expression of EZH2 mRNA was increased in diabetic ssEVs. EZH2‐specific inhibitor significantly reversed diabetic ssEVs‐enhanced expression of EZH2 and H3K27me3, impaired expression of angiogenic factors, and improved blood perfusion and vessel density in ischemic hind limb of C57BL/6J mice. Finally, EZH2 inactivation repressed diabetic ssEVs‐induced H3K27me3 expression at promoter of pro‐angiogenic genes. CONCLUSIONS: Diabetic ssEVs impair the angiogenic property of MVECs via, at least partially, transferring EZH2 mRNA to MVECs, thus inducing the epigenetic mechanism involving EZH2‐enhanced expression of H3K27me3 and consequent silencing of pro‐angiogenic genes. Our findings unravel the cellular mechanism and expand the scope of bloodborne substances that impair MVEC function in diabetes mellitus. John Wiley and Sons Inc. 2021-05-14 /pmc/articles/PMC8200714/ /pubmed/33988033 http://dx.doi.org/10.1161/JAHA.120.019755 Text en © 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Research Cheng, Zhongjian Naga Srikanth Garikipati, Venkata Truongcao, May M. Cimini, Maria Huang, Grace Wang, Chunlin Benedict, Cindy Gonzalez, Carolina Mallaredy, Vandana Goukassian, David A. Verma, Suresh K. Kishore, Raj Serum‐Derived Small Extracellular Vesicles From Diabetic Mice Impair Angiogenic Property of Microvascular Endothelial Cells: Role of EZH2 |
title | Serum‐Derived Small Extracellular Vesicles From Diabetic Mice Impair Angiogenic Property of Microvascular Endothelial Cells: Role of EZH2 |
title_full | Serum‐Derived Small Extracellular Vesicles From Diabetic Mice Impair Angiogenic Property of Microvascular Endothelial Cells: Role of EZH2 |
title_fullStr | Serum‐Derived Small Extracellular Vesicles From Diabetic Mice Impair Angiogenic Property of Microvascular Endothelial Cells: Role of EZH2 |
title_full_unstemmed | Serum‐Derived Small Extracellular Vesicles From Diabetic Mice Impair Angiogenic Property of Microvascular Endothelial Cells: Role of EZH2 |
title_short | Serum‐Derived Small Extracellular Vesicles From Diabetic Mice Impair Angiogenic Property of Microvascular Endothelial Cells: Role of EZH2 |
title_sort | serum‐derived small extracellular vesicles from diabetic mice impair angiogenic property of microvascular endothelial cells: role of ezh2 |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200714/ https://www.ncbi.nlm.nih.gov/pubmed/33988033 http://dx.doi.org/10.1161/JAHA.120.019755 |
work_keys_str_mv | AT chengzhongjian serumderivedsmallextracellularvesiclesfromdiabeticmiceimpairangiogenicpropertyofmicrovascularendothelialcellsroleofezh2 AT nagasrikanthgarikipativenkata serumderivedsmallextracellularvesiclesfromdiabeticmiceimpairangiogenicpropertyofmicrovascularendothelialcellsroleofezh2 AT truongcaomaym serumderivedsmallextracellularvesiclesfromdiabeticmiceimpairangiogenicpropertyofmicrovascularendothelialcellsroleofezh2 AT ciminimaria serumderivedsmallextracellularvesiclesfromdiabeticmiceimpairangiogenicpropertyofmicrovascularendothelialcellsroleofezh2 AT huanggrace serumderivedsmallextracellularvesiclesfromdiabeticmiceimpairangiogenicpropertyofmicrovascularendothelialcellsroleofezh2 AT wangchunlin serumderivedsmallextracellularvesiclesfromdiabeticmiceimpairangiogenicpropertyofmicrovascularendothelialcellsroleofezh2 AT benedictcindy serumderivedsmallextracellularvesiclesfromdiabeticmiceimpairangiogenicpropertyofmicrovascularendothelialcellsroleofezh2 AT gonzalezcarolina serumderivedsmallextracellularvesiclesfromdiabeticmiceimpairangiogenicpropertyofmicrovascularendothelialcellsroleofezh2 AT mallaredyvandana serumderivedsmallextracellularvesiclesfromdiabeticmiceimpairangiogenicpropertyofmicrovascularendothelialcellsroleofezh2 AT goukassiandavida serumderivedsmallextracellularvesiclesfromdiabeticmiceimpairangiogenicpropertyofmicrovascularendothelialcellsroleofezh2 AT vermasureshk serumderivedsmallextracellularvesiclesfromdiabeticmiceimpairangiogenicpropertyofmicrovascularendothelialcellsroleofezh2 AT kishoreraj serumderivedsmallextracellularvesiclesfromdiabeticmiceimpairangiogenicpropertyofmicrovascularendothelialcellsroleofezh2 |