Irradiation induces different inflammatory and thrombotic responses in carotid arteries of wildtype C57BL/6J and atherosclerosis-prone ApoE−/− mice

Background and purpose: We have previously shown that irradiation to the carotid arteries of hypercholesterolemic ApoE−/− mice accelerated the development of macrophage-rich, inflammatory atherosclerotic lesions. We now investigated the mechanism underlying the development of radiation-induced atherosclerosis. Materials and methods: ApoE−/− and wildtype C57BL/6J mice received 0, 8 or 14 Gy to the neck and the carotid arteries were harvested 1 day, 1 or 4 weeks later. Immunohistochemical stainings were performed to evaluate well-known inflammatory and thrombotic molecules. A hypothesis-generating approach was used to compare gene expression profiles of irradiated and unirradiated carotid arteries. Results: Basal levels of endothelial VCAM-1 and thrombomodulin immunoexpression were higher in ApoE−/− mice than in C57BL/6J mice. At 1 week after 14 Gy VCAM-1 immunoexpression was decreased in ApoE−/− mice, whereas ICAM-1 immunoexpression was decreased at 1 and 4 weeks after 14 Gy in C57BL/6J mice. Thrombomodulin and tissue factor immunoexpression were elevated at 4 weeks after 14 Gy in ApoE−/− mice and reduced in C57BL/6J mice. There were no changes in immunoexpression of eNOS, MCP-1 or endoglin. Several canonical pathways were differentially expressed after irradiation, including tight junction pathways, leukocyte extravasation signaling and PI3K/AKT signaling. Conclusion: ApoE−/− and C57BL/6J mice respond differently to irradiation. The thrombotic pathways were activated after irradiation in ApoE−/− mice only. Genes involved in tight junction regulation were up-regulated in ApoE−/− mice and decreased in C57BL/6J mice. These factors may have contributed to fatty-streak formation in ApoE−/− mice.