PLAC8-Mediated Activation of NOX4 Signalling Restores Angiogenic Function of Endothelial Colony-Forming Cells in Experimental Hypoxia
Ischaemic cardiovascular disease is associated with tissue hypoxia as a significant determinant of angiogenic dysfunction and adverse remodelling. While cord blood-derived endothelial colony-forming cells (CB-ECFCs) hold clear therapeutic potential due to their enhanced angiogenic and proliferative...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-09-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/12/18/2220 |
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| author | Shun Hay Pun Karla M. O’Neill Kevin S. Edgar Eleanor K. Gill Arya Moez Hojjat Naderi-Meshkin Sudhir B. Malla Michelle B. Hookham Mohammed Alsaggaf Vinuthna Vani Madishetti Bianca Botezatu William King Coy Brunssen Henning Morawietz Philip D. Dunne Derek P. Brazil Reinhold J. Medina Chris J. Watson David J. Grieve |
| author_facet | Shun Hay Pun Karla M. O’Neill Kevin S. Edgar Eleanor K. Gill Arya Moez Hojjat Naderi-Meshkin Sudhir B. Malla Michelle B. Hookham Mohammed Alsaggaf Vinuthna Vani Madishetti Bianca Botezatu William King Coy Brunssen Henning Morawietz Philip D. Dunne Derek P. Brazil Reinhold J. Medina Chris J. Watson David J. Grieve |
| author_sort | Shun Hay Pun |
| collection | DOAJ |
| description | Ischaemic cardiovascular disease is associated with tissue hypoxia as a significant determinant of angiogenic dysfunction and adverse remodelling. While cord blood-derived endothelial colony-forming cells (CB-ECFCs) hold clear therapeutic potential due to their enhanced angiogenic and proliferative capacity, their impaired functionality within the disease microenvironment represents a major barrier to clinical translation. The aim of this study was to define the specific contribution of NOX4 NADPH oxidase, which we previously reported as a key CB-ECFC regulator, to hypoxia-induced dysfunction and its potential as a therapeutic target. CB-ECFCs exposed to experimental hypoxia demonstrated downregulation of NOX4-mediated reactive oxygen species (ROS) signalling linked with a reduced tube formation, which was partially restored by NOX4 plasmid overexpression. siRNA knockdown of placenta-specific 8 (PLAC8), identified by microarray analysis as an upstream regulator of NOX4 in hypoxic versus normoxic CB-ECFCs, enhanced tube formation, NOX4 expression and hydrogen peroxide generation, and induced several key transcription factors associated with downstream Nrf2 signalling. Taken together, these findings indicated that activation of the PLAC8–NOX4 signalling axis improved CB-ECFC angiogenic functions in experimental hypoxia, highlighting this pathway as a potential target for protecting therapeutic cells against the ischaemic cardiovascular disease microenvironment. |
| first_indexed | 2024-03-10T22:56:37Z |
| format | Article |
| id | doaj.art-c401b027209144cda01f2bdf818f87be |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T22:56:37Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-c401b027209144cda01f2bdf818f87be2023-11-19T09:58:59ZengMDPI AGCells2073-44092023-09-011218222010.3390/cells12182220PLAC8-Mediated Activation of NOX4 Signalling Restores Angiogenic Function of Endothelial Colony-Forming Cells in Experimental HypoxiaShun Hay Pun0Karla M. O’Neill1Kevin S. Edgar2Eleanor K. Gill3Arya Moez4Hojjat Naderi-Meshkin5Sudhir B. Malla6Michelle B. Hookham7Mohammed Alsaggaf8Vinuthna Vani Madishetti9Bianca Botezatu10William King11Coy Brunssen12Henning Morawietz13Philip D. Dunne14Derek P. Brazil15Reinhold J. Medina16Chris J. Watson17David J. Grieve18Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast BT9 7AE, UKWellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast BT9 7AE, UKWellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast BT9 7AE, UKWellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast BT9 7AE, UKWellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast BT9 7AE, UKWellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast BT9 7AE, UKPatrick G Johnston Centre for Cancer Research, Queen’s University, Belfast BT9 7AE, UKWellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast BT9 7AE, UKWellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast BT9 7AE, UKWellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast BT9 7AE, UKWellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast BT9 7AE, UKWellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast BT9 7AE, UKDivision of Vascular Endothelium and Microcirculation, TUD Dresden University of Technology, 01307 Dresden, GermanyDivision of Vascular Endothelium and Microcirculation, TUD Dresden University of Technology, 01307 Dresden, GermanyPatrick G Johnston Centre for Cancer Research, Queen’s University, Belfast BT9 7AE, UKWellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast BT9 7AE, UKWellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast BT9 7AE, UKWellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast BT9 7AE, UKWellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast BT9 7AE, UKIschaemic cardiovascular disease is associated with tissue hypoxia as a significant determinant of angiogenic dysfunction and adverse remodelling. While cord blood-derived endothelial colony-forming cells (CB-ECFCs) hold clear therapeutic potential due to their enhanced angiogenic and proliferative capacity, their impaired functionality within the disease microenvironment represents a major barrier to clinical translation. The aim of this study was to define the specific contribution of NOX4 NADPH oxidase, which we previously reported as a key CB-ECFC regulator, to hypoxia-induced dysfunction and its potential as a therapeutic target. CB-ECFCs exposed to experimental hypoxia demonstrated downregulation of NOX4-mediated reactive oxygen species (ROS) signalling linked with a reduced tube formation, which was partially restored by NOX4 plasmid overexpression. siRNA knockdown of placenta-specific 8 (PLAC8), identified by microarray analysis as an upstream regulator of NOX4 in hypoxic versus normoxic CB-ECFCs, enhanced tube formation, NOX4 expression and hydrogen peroxide generation, and induced several key transcription factors associated with downstream Nrf2 signalling. Taken together, these findings indicated that activation of the PLAC8–NOX4 signalling axis improved CB-ECFC angiogenic functions in experimental hypoxia, highlighting this pathway as a potential target for protecting therapeutic cells against the ischaemic cardiovascular disease microenvironment.https://www.mdpi.com/2073-4409/12/18/2220NOX4 NADPH oxidaseplacenta-specific 8endothelial colony-forming cellshypoxiaangiogenesisreactive oxygen species |
| spellingShingle | Shun Hay Pun Karla M. O’Neill Kevin S. Edgar Eleanor K. Gill Arya Moez Hojjat Naderi-Meshkin Sudhir B. Malla Michelle B. Hookham Mohammed Alsaggaf Vinuthna Vani Madishetti Bianca Botezatu William King Coy Brunssen Henning Morawietz Philip D. Dunne Derek P. Brazil Reinhold J. Medina Chris J. Watson David J. Grieve PLAC8-Mediated Activation of NOX4 Signalling Restores Angiogenic Function of Endothelial Colony-Forming Cells in Experimental Hypoxia Cells NOX4 NADPH oxidase placenta-specific 8 endothelial colony-forming cells hypoxia angiogenesis reactive oxygen species |
| title | PLAC8-Mediated Activation of NOX4 Signalling Restores Angiogenic Function of Endothelial Colony-Forming Cells in Experimental Hypoxia |
| title_full | PLAC8-Mediated Activation of NOX4 Signalling Restores Angiogenic Function of Endothelial Colony-Forming Cells in Experimental Hypoxia |
| title_fullStr | PLAC8-Mediated Activation of NOX4 Signalling Restores Angiogenic Function of Endothelial Colony-Forming Cells in Experimental Hypoxia |
| title_full_unstemmed | PLAC8-Mediated Activation of NOX4 Signalling Restores Angiogenic Function of Endothelial Colony-Forming Cells in Experimental Hypoxia |
| title_short | PLAC8-Mediated Activation of NOX4 Signalling Restores Angiogenic Function of Endothelial Colony-Forming Cells in Experimental Hypoxia |
| title_sort | plac8 mediated activation of nox4 signalling restores angiogenic function of endothelial colony forming cells in experimental hypoxia |
| topic | NOX4 NADPH oxidase placenta-specific 8 endothelial colony-forming cells hypoxia angiogenesis reactive oxygen species |
| url | https://www.mdpi.com/2073-4409/12/18/2220 |
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