Chronic Gamma-Irradiation Induces a Dose-Rate-Dependent Pro-inflammatory Response and Associated Loss of Function in Human Umbilical Vein Endothelial Cells

Abstract

A central question in radiation protection research is dose and dose-rate relationship for radiation-induced cardiovascular diseases. The response of endothelial cells to different low dose rates may contribute to help estimate risks for cardiovascular diseases by providing mechanistic understanding. In this study we investigated whether chronic low-dose-rate radiation exposure had an effect on the inflammatory response of endothelial cells and their function. Human umbilical vein endothelial cells (HUVECs) were chronically exposed to radiation at a dose of 1.4 mGy/h or 4.1 mGy/h for 1, 3, 6 or 10 weeks. We determined the pro-inflammatory profile of HUVECs before and during radiation exposure, and investigated the functional consequences of this radiation exposure by measuring their capacity to form vascular networks in matrigel. Expression levels of adhesion molecules such as E-selectin, ICAM-1 and VCAM-1, and the release of pro-inflammatory cytokines such as MCP-1, IL-6 and TNF-α were analyzed. When a total dose of 2 Gy was given at a rate of 4.1 mGy/h, we observed an increase in IL-6 and MCP-1 release into the cell culture media, but this was not observed at 1.4 mGy/h. The increase in the inflammatory profile induced at the dose rate of 4.1 mGy/h was also correlated with a decrease in the capacity of the HUVECs to form a vascular network in matrigel. Our results suggest that dose rate is an important parameter in the alteration of HUVEC inflammatory profile and function.

Differential Impact of Single-Dose Fe Ion and X-Ray Irradiation on Endothelial Cell Transcriptomic and Proteomic Responses

“…The pro-inflammatory effect of X-ray exposure was previously evidenced in the same in vitro model (Baselet et al, 2017 ). In accordance, others observed elevated IL-6 and IL-8 levels in 2–10 Gy X-ray-irradiated EC cultures (Meeren et al, 1997 ), elevated IL-6 levels in EC cultures after chronic irradiation with a total dose of 2 Gy (Ebrahimian et al, 2015 ) and elevated blood levels of IL-6 were detected in A-bomb survivors (Hayashi et al, 2003 ). These changes were previously demonstrated to increase EC adhesiveness to monocytes 1 day after exposure to X-ray doses higher than 5 Gy (Khaled et al, 2012 ).…”

Chronic Exposure to External Low-Dose Gamma Radiation Induces an Increase in Anti-inflammatory and Anti-oxidative Parameters Resulting in Atherosclerotic Plaque Size Reduction in ApoE–/–Mice

“…Our current study is in line with some of the previously reported results, and we demonstrated that chronic external low-dose (150 mGy) irradiation at a low-dose rate (28 iGy.h-1) induces a protective effect in atherosclerotic lesions. The importance of the dose, as well as the dose rate, even after chronic low-dose exposure, was confirmed in animal models (19) and in a cultured endothelial cell model (24,36).…”

“…These results suggest that low doses of radiation have an effect that is opposite of that from high doses in atherosclerosis development, and that dose rate is a very important parameter to consider. Dose rate dependent of inflammatory response and endothelial cell function has been demonstrated recently in published in vitro experiments (24).…”

Gamma Low-Dose-Rate Ionizing Radiation Stimulates Adaptive Functional and Molecular Response in Human Aortic Endothelial Cells in a Threshold-, Dose-, and Dose Rate–Dependent Manner

“…In vitro studies showed that chronic LDR delivered at 4.1 mGy/h had harmful effects on human umbilical vein endothelial cells (HUVECs; premature senescence, loss of capacity to form vascular networks, and secretion of pro-inflammatory molecules) when the total dose was >2 Gy, while a lower dose rate (1.4 mGy/h) did not induce damage even at a dose of 2 Gy. 17 , 18 Moreover, Rombout et al showed that a low dose (0.05 Gy) induced subtle increases in DNA double-strand breaks in HUVECs compared to high doses. 19 Also, Rödel et al showed that acute radiation doses in the range of 0.3 to 0.7 Gy induced anti-inflammatory effects on human endothelial cells (EA.Hy926) by stimulating protein and mitochondrial RNA (mRNA) levels of transforming growth factor-β 1 (TGF-β1), leading to downregulation of leukocyte adhesion .…”