HIF-1α Deletion in the Endothelium, but Not in the Epithelium, Protects From Radiation-Induced Enteritis

Aurore Toullec; Valérie Buard; Emilie Rannou; Georges Tarlet; Olivier Guipaud; Sylvie Robine; M Luisa Iruela-Arispe; Agnès François; Fabien Milliat

doi:10.1016/j.jcmgh.2017.08.001

HIF-1α Deletion in the Endothelium, but Not in the Epithelium, Protects From Radiation-Induced Enteritis

Cell Mol Gastroenterol Hepatol. 2017 Aug 16;5(1):15-30. doi: 10.1016/j.jcmgh.2017.08.001. eCollection 2018.

Authors

Aurore Toullec¹, Valérie Buard¹, Emilie Rannou^{1

2}, Georges Tarlet¹, Olivier Guipaud¹, Sylvie Robine³, M Luisa Iruela-Arispe², Agnès François¹, Fabien Milliat¹

Affiliations

¹ Research Laboratory of Radiobiology and Radiopathology, Institute for Radiological Protection and Nuclear Safety, Fontenay-aux-Roses, France.
² Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, California.
³ Curie Institute, Paris, France.

Abstract

Background & aims: Radiation therapy in the pelvic area is associated with side effects that impact the quality of life of cancer survivors. Interestingly, the gastrointestinal tract is able to adapt to significant changes in oxygen availability, suggesting that mechanisms related to hypoxia sensing help preserve tissue integrity in this organ. However, hypoxia-inducible factor (HIF)-dependent responses to radiation-induced gut toxicity are unknown. Radiation-induced intestinal toxicity is a complex process involving multiple cellular compartments. Here, we investigated whether epithelial or endothelial tissue-specific HIF-1α deletion could affect acute intestinal response to radiation.

Methods: Using constitutive and inducible epithelial or endothelial tissue-specific HIF-1α deletion, we evaluated the consequences of epithelial or endothelial HIF-1α deletion on radiation-induced enteritis after localized irradiation. Survival, radiation-induced tissue injury, molecular inflammatory profile, tissue hypoxia, and vascular injury were monitored.

Results: Surprisingly, epithelium-specific HIF-1α deletion does not alter radiation-induced intestinal injury. However, irradiated VECad-Cre^+/-HIF-1α^FL/FL mice present with lower radiation-induced damage, showed a preserved vasculature, reduced hypoxia, and reduced proinflammatory response compared with irradiated HIF-1α^FL/FL mice.

Conclusions: We demonstrate in vivo that HIF-1α impacts radiation-induced enteritis and that this role differs according to the targeted cell type. Our work provides a new role for HIF-1α and endothelium-dependent mechanisms driving inflammatory processes in gut mucosae. Results presented show that effects on normal tissues have to be taken into account in approaches aiming to modulate hypoxia or hypoxia-related molecular mechanisms.

Keywords: EndoMT, endothelial-to-mesenchymal transition; Endothelium; HIF, hypoxia-inducible factor; HIF-1α; HIF-1αFl/FL, HIF-1α floxed mice; HIMEC, human intestinal microvascular endothelial cells; HUVEC, human umbilical vein endothelial cells; IL, interleukin; PAI-1, plasminogen activator inhibitor type-1; PCR, polymerase chain reaction; ROSA, ROSA26R LacZ reporter mice; Radiation; Sham-IR, sham-irradiation; TBI, total body irradiation; VECad-Cre, VE-cadherin-Cre mice.