Oncotarget

Research Papers:

Ionising radiation increases permeability of endothelium through ADAM10-mediated cleavage of VE-cadherin

Sylwia Kabacik _ and Ken Raj

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2017; 8:82049-82063. https://doi.org/10.18632/oncotarget.18282

Metrics: PDF 1850 views  |   HTML 2785 views  |   ?  


Abstract

Sylwia Kabacik1 and Ken Raj1

1Radiation Effects Department, Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Chilton, UK

Correspondence to:

Sylwia Kabacik, email: [email protected]

Keywords: permeability, VE-cadherin, ADAM10, cell junctions, ionising radiation

Received: February 14, 2017     Accepted: May 03, 2017     Published: May 30, 2017

ABSTRACT

The association between ionising radiation (IR) exposure and risk of cardiovascular diseases (CVD) is well documented, but the underlying mechanism is still poorly understood. As atherosclerotic plaques are the most common cause of CVD, we investigated the effects of IR on one of the critical parameters for atherosclerotic plaque formation – endothelium permeability to macromolecules.

We used endothelial cells from human coronary artery as a model of the endothelial layer. Our results show that exposure of this endothelial layer to IR increased its permeability to macromolecules of various sizes in a dose-dependent manner. Immunofluorescence analysis revealed disruption of cell junctions caused by decreased amounts of two junction proteins, one of which is vascular endothelial cadherin (VE-cadherin). The reduction in the level of this protein was not due to diminished transcription but to protein processing instead. We observed a radiation dose-dependent increase in the cleavage of VE-cadherin by ADAM10. This was not mediated through the canonical VEGF route but was instead accompanied by intra-cellular calcium release. Importantly, inhibition of ADAM10 activity rescued IR-induced permeability.

Our observations demonstrate that exposure to IR activates ADAM10 to cleave VE-cadherin leading to augmented endothelium permeability; a feature that can lead to the development of atherosclerotic plaques and increase the risk of cardiovascular disease.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 18282