In vivo evidence for an endothelium-dependent mechanism in radiation-induced normal tissue injury

Emilie Rannou, Agnès François, Aurore Toullec, Olivier Guipaud, Valérie Buard, Georges Tarlet, Elodie Mintet, Cyprien Jaillet, Maria Luisa Iruela-Arispe, Marc Benderitter, Jean Christophe Sabourin, Fabien Milliat*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

The pathophysiological mechanism involved in side effects of radiation therapy, and especially the role of the endothelium remains unclear. Previous results showed that plasminogen activator inhibitor-type 1 (PAI-1) contributes to radiation-induced intestinal injury and suggested that this role could be driven by an endothelium-dependent mechanism. We investigated whether endothelial-specific PAI-1 deletion could affect radiation-induced intestinal injury. We created a mouse model with a specific deletion of PAI-1 in the endothelium (PAI-1KO endo) by a Cre-LoxP system. In a model of radiation enteropathy, survival and intestinal radiation injury were followed as well as intestinal gene transcriptional profile and inflammatory cells intestinal infiltration. Irradiated PAI-1KO endo mice exhibited increased survival, reduced acute enteritis severity and attenuated late fibrosis compared with irradiated PAI-1 flx/flx mice. Double E-cadherin/TUNEL labeling confirmed a reduced epithelial cell apoptosis in irradiated PAI-1KO endo. High-throughput gene expression combined with bioinformatic analyses revealed a putative involvement of macrophages. We observed a decrease in CD68 + cells in irradiated intestinal tissues from PAI-1KO endo mice as well as modifications associated with M1/M2 polarization. This work shows that PAI-1 plays a role in radiation-induced intestinal injury by an endothelium-dependent mechanism and demonstrates in vivo that the endothelium is directly involved in the progression of radiation-induced enteritis.

Original languageEnglish (US)
Article number15738
JournalScientific reports
Volume5
DOIs
StatePublished - Oct 29 2015

ASJC Scopus subject areas

  • General

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