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

Abstract

Background & AimsRadiation 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.MethodsUsing 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.ResultsSurprisingly, epithelium-specific HIF-1α deletion does not alter radiation-induced intestinal injury. However, irradiated VECad-Cre+/-HIF-1αFL/FL mice present with lower radiation-induced damage, showed a preserved vasculature, reduced hypoxia, and reduced proinflammatory response compared with irradiated HIF-1αFL/FL mice.ConclusionsWe 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.

The importance of the vascular endothelial barrier in the immune-inflammatory response induced by radiotherapy

“…98 Recently, it has been shown that endothelial hypoxia-inducible factor (HIF)−1α deletion confers resistance to radiation-induced enteritis, whereas similar deletion in intestinal epithelium does not, suggesting new functions of endothelial HIF-1α-signalling pathways as mediators of mucosal-inflammatory processes. 99 On the other hand, it has been demonstrated in vivo that the endothelium is directly involved in the progression of radiation-induced enteritis by using a mouse model harbouring an endothelium-specific deletion of the serpinE1 gene, which encodes the plasminogen activator inhibitor-type 1 (PAI-1). 100…”

Identification of a novel HIF-1α-αMβ2Integrin-NETosis axis in fibrotic interstitial lung disease

“…Whilst epithelium-specific HIF-1α deletion has no effect upon radiation-induced enteritis, mice with endothelium-specific HIF-1α deletions present with reduced intestinal damage 64 . HIF-1α is known to contribute to the pathology of pulmonary hypertension 65,66 , with some work specifically interrogating endothelial HIF signalling 67 .…”

Identification of a Novel HIF-1α-αMβ2 Integrin-NET Axis in Fibrotic Interstitial Lung Disease

“…HIF-1α is more readily found in the mouse bleomycin model of PF raising the question of differences between the two species and insults (77). Whilst epithelium-specific HIF-1α deletion has no effect upon radiation-induced enteritis, mice with endothelium-specific HIF-1α deletions present with reduced intestinal damage (78). HIF-1α is known to contribute to the pathology of pulmonary hypertension (79,80), with some work specifically interrogating endothelial HIF signaling (81).…”