PLAC8-Mediated Activation of NOX4 Signalling Restores Angiogenic Function of Endothelial Colony-Forming Cells in Experimental Hypoxia

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

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.
Original languageEnglish
Article number2220
JournalCells
Volume12
Issue number18
Early online date06 Sept 2023
DOIs
Publication statusEarly online date - 06 Sept 2023

Keywords

  • NOX4 NADPH oxidase
  • endothelial colony-forming cells
  • angiogenesis
  • placenta-specific 8
  • reactive oxygen species
  • hypoxia

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