In vivo evidence for an endothelium-dependent mechanism in radiation-induced normal tissue injury.
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.
Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Department of Radiobiology and Epidemiology (SRBE), Research on Radiobiology and Radiopathology Laboratory (L3R), Fontenay-aux-Roses, 92260, France.
Emilie
E
Rannou
Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Department of Radiobiology and Epidemiology (SRBE), Research on Radiobiology and Radiopathology Laboratory (L3R), Fontenay-aux-Roses, 92260, France.
Agnès
A
François
Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Department of Radiobiology and Epidemiology (SRBE), Research on Radiobiology and Radiopathology Laboratory (L3R), Fontenay-aux-Roses, 92260, France.
Aurore
A
Toullec
Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Department of Radiobiology and Epidemiology (SRBE), Research on Radiobiology and Radiopathology Laboratory (L3R), Fontenay-aux-Roses, 92260, France.
Olivier
O
Guipaud
Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Department of Radiobiology and Epidemiology (SRBE), Research on Radiobiology and Radiopathology Laboratory (L3R), Fontenay-aux-Roses, 92260, France.
Valérie
V
Buard
Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Department of Radiobiology and Epidemiology (SRBE), Research on Radiobiology and Radiopathology Laboratory (L3R), Fontenay-aux-Roses, 92260, France.
Georges
G
Tarlet
Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Department of Radiobiology and Epidemiology (SRBE), Research on Radiobiology and Radiopathology Laboratory (L3R), Fontenay-aux-Roses, 92260, France.
Elodie
E
Mintet
Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Department of Radiobiology and Epidemiology (SRBE), Research on Radiobiology and Radiopathology Laboratory (L3R), Fontenay-aux-Roses, 92260, France.
Cyprien
C
Jaillet
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles.
Maria Luisa
ML
Iruela-Arispe
Institut de Radioprotection et de Sureté Nucléaire (IRSN), Department of Radiobiology and Epidemiology (SRBE), Fontenay-aux-Roses, France.
Marc
M
Benderitter
Department of Pathology, Rouen University Hospital, France.
Jean-Christophe
JC
Sabourin
Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Department of Radiobiology and Epidemiology (SRBE), Research on Radiobiology and Radiopathology Laboratory (L3R), Fontenay-aux-Roses, 92260, France.
Fabien
F
Milliat
D000818:Animals; D002470:Cell Survival / Q000235:genetics / Q000528:radiation effects; D004727:Endothelium / Q000378:metabolism* / Q000473:pathology; D005720:Gamma Rays / Q000009:adverse effects*; D005786:Gene Expression Regulation / Q000528:radiation effects*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011833:Radiation Injuries, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058258:Serpin E2 / Q000235:genetics / Q000378:metabolism*
D058258:Serpin E2; C511869:Serpine2 protein, mouse