Abstract
The current study evaluated the role of Hey2 transcription factor in radiation-induced endothelial-to-mesenchymal transition (EndoMT) and its impact on radiation-induced tissue damage in mice. Phenotypic modifications of irradiated, Hey2 siRNA- and Hey2 vector plasmid-transfected human umbilical vein endothelial cells (HUVECs) resembling EndoMT were monitored by qPCR, immunocytochemistry and western blots. Subsequently, in mice, a Cre-LoxP strategy for inactivation of Hey2 specifically in the endothelium was used to study the biological consequences. Total body irradiation and radiation proctitis were monitored to investigate the impact of conditional Hey2 deletion on intestinal stem cells and microvascular compartment radiosensitivity, EndoMT and rectal damage severity. We found that EndoMT occurs in irradiated HUVECs with concomitant Hey2 mRNA and protein increase. While Hey2 silencing has no effect on radiation-induced EndoMT in vitro, Hey2 overexpression is sufficient to induce phenotypic conversion of endothelial cells. In mice, the conditional deletion of Hey2 reduces EndoMT frequency and the severity of rectal tissue damage. Our data indicate that the reduction in mucosal damage occurs through decline in stem/clonogenic epithelial cell loss mediated by microvascular protection. EndoMT is involved in radiation proctitis and this study demonstrates that a strategy based on the reduction of EndoMT mitigates intestinal tissue damage.
Highlights
About half of cancer patients undergo radiation therapy as part of their cancer treatment
We show that ionizing radiation induces a phenotypic conversion of human umbilical vein endothelial cells (HUVECs) that resembles endothelial-to-mesenchymal transition (EndoMT)
The endothelial compartment is present in normal tissues as well as in tumors, and advances in the radiobiology of endothelial cells may be determinant in understanding how tumors and healthy tissues respond to radiation therapy[3, 33]
Summary
About half of cancer patients undergo radiation therapy as part of their cancer treatment. Irradiated endothelial cells undergo apoptosis or may acquire a long-lasting procoagulant and antifibrinolytic phenotype with sustained immune cell recruitment, which participates in the development of tissue damage. Rieder et al.[14] identified EndoMT as a potential participant in human gut inflammation and in a preclinical model of colonic fibrosis in mice, demonstrating both in vitro and in vivo that inflammatory signals in the gut are able to trigger phenotypic conversion of endothelial cells to mesenchymal-like cells. We report that irradiation is a stimulus sufficient to induce EndoMT in vitro in human umbilical vein endothelial cells (HUVECs), associated with increased Hey[2] mRNA and protein expression. We propose reducing EndoMT as a possible strategy to mitigate radiation-induced damage to normal digestive tissue
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