title: Identification of Endothelial-to-Mesenchymal Transition as a Potential Participant in Radiation Proctitis.
abstract: The endothelial-to-mesenchymal transition (EndoMT) is a crucial cellular process during heart development necessary to the formation of cardiac valves. This embryonic process reappears in several pathological situations, such as vascular injury or organ fibrosis of various etiologies, as a mediator of extracellular matrix-producing cells. Because radiation induces both vascular damage and fibrosis, we investigated whether radiation exposure induces EndoMT in primary human intestinal microvascular endothelial cells (HIMECs) and whether EndoMT contributes to radiation-induced rectal damage in humans and in a preclinical model of radiation proctitis in mice. Irradiated HIMECs show phenotypic hallmarks of radiation-induced endothelial cell activation in vitro. Moreover, HIMECs undergo changes in molecular expression pattern compatible with EndoMT, with up-regulation of mesenchymal markers and down-regulation of endothelial markers via transforming growth factor/Smad pathway activation. In vivo, EndoMT readily occurs in the human rectum after radiation therapy for rectal adenocarcinoma. Finally, EndoMT was observed in rectal mucosal and submucosal microvessels in a preclinical model of radiation proctitis in Tie2-green fluorescent protein reporter-expressing mice all along radiation proctitis development, also associated with transforming growth factor/Smad pathway activation. In conclusion, radiation-induced cell activation and tissue inflammation constitute a setting that fosters the phenotypic conversion of endothelial cells into mesenchymal cells. Therefore, EndoMT is identified as a potential participant in radiation-induced gut damage and may represent an interesting therapeutic target in cases of radiation-induced pelvic disease.
authors.affiliation: Department of Radiobiology and Epidemiology, Radiobiology and Radiopathology Research Laboratory, Fontenay-aux-Roses, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Mintet
authors.affiliation: Department of Radiobiology and Epidemiology, Radiobiology and Radiopathology Research Laboratory, Fontenay-aux-Roses, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Rannou
authors.affiliation: Department of Radiobiology and Epidemiology, Radiobiology and Radiopathology Research Laboratory, Fontenay-aux-Roses, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Buard
authors.affiliation: Department of Pathobiology, Digestive Disease Institute, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio.
authors.forename: Gail
authors.initials: G
authors.lastname: West
authors.affiliation: Department of Radiobiology and Epidemiology, Radiobiology and Radiopathology Research Laboratory, Fontenay-aux-Roses, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Guipaud
authors.affiliation: Department of Radiobiology and Epidemiology, Radiobiology and Radiopathology Research Laboratory, Fontenay-aux-Roses, France.
authors.forename: Georges
authors.initials: G
authors.lastname: Tarlet
authors.affiliation: Department of Pathology, Rouen University Hospital, Rouen, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Sabourin
authors.affiliation: Department of Radiobiology and Epidemiology, Institut de Radioprotection et de Sûreté Nucléaire, Fontenay-aux-Roses, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Benderitter
authors.affiliation: Department of Pathobiology, Digestive Disease Institute, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio.
authors.forename: Claudio
authors.initials: C
authors.lastname: Fiocchi
authors.affiliation: Department of Radiobiology and Epidemiology, Radiobiology and Radiopathology Research Laboratory, Fontenay-aux-Roses, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Milliat
authors.affiliation: Department of Radiobiology and Epidemiology, Radiobiology and Radiopathology Research Laboratory, Fontenay-aux-Roses, France. Electronic address: agnes.francois@irsn.fr.
authors.forename: Agnès
authors.initials: A
authors.lastname: François
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005109:Extracellular Matrix / Q000378:metabolism*; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D051379:Mice; D011349:Proctitis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011832:Radiation Injuries / Q000378:metabolism*; D015854:Up-Regulation / Q000528:radiation effects
chemical_list: D015415:Biomarkers