Radiation-stimulated translocation of CD166 and CRYAB to the endothelial surface provides potential vascular targets on irradiated brain arteriovenous malformations

Lucinda S. McRobb*, Matthew J. McKay, Andrew J. Gauden, Vivienne S. Lee, Sinduja Subramanian, Santhosh George Thomas, Markus K. H. Wiedmann, Vaughan Moutrie, Michael Grace, Zhenjun Zhao, Mark P. Molloy, Marcus A. Stoodley

*Corresponding author for this work

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Abstract

Vascular targeting with pro-thrombotic antibody-conjugates is a promising biological treatment for brain arteriovenous malformations (bAVMs). However, targeted drug delivery relies on the identification of unique or overexpressed markers on the surface of a target cell. In the absence of inherent biological markers, stereotactic radiosurgery may be used to prime induction of site-specific and targetable molecular changes on the endothelial surface. To investigate lumen-accessible, endothelial targets induced by radiation, we combined Gamma knife surgery in an AVM animal model with in vivo biotin-labeling and comparative proteomics. Two proteins, αB-crystallin (CRYAB)—a small heat shock protein that normally acts as an intracellular chaperone to misfolded proteins—and activated leukocyte cell adhesion molecule CD166, were further validated for endothelial surface expression after irradiation. Immunostaining of endothelial cells in vitro and rat AVM tissue ex vivo confirmed de novo induction of CRYAB following irradiation (20 Gy). Western analysis demonstrated that CRYAB accumulated intracellularly as a 20 kDa monomer, but, at the cell surface, a novel 65 kDa protein was observed, suggesting radiation stimulates translocation of an atypical CRYAB isoform. In contrast, CD166 had relatively high expression in non-irradiated cells, localized predominantly to the lateral surfaces. Radiation increased CD166 surface exposure by inducing translocation from intercellular junctions to the apical surface without significantly altering total protein levels. These findings reinforce the dynamic molecular changes induced by radiation exposure, particularly at the cell surface, and support further investigation of radiation as a priming mechanism and these molecules as putative targets for focused drug delivery in irradiated tissue.

Original languageEnglish
Article number5830
Pages (from-to)1-13
Number of pages13
JournalInternational Journal of Molecular Sciences
Volume20
Issue number23
DOIs
Publication statusPublished - Dec 2019

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Copyright the Author(s) 2019. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • Brain arteriovenous malformation
  • Endothelial cells
  • Ionizing radiation
  • Proteomics
  • Stereotactic radiosurgery
  • Vascular targeting

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