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(American Journal of Pathology. 2006;168:649-658.)
© 2006 American Society for Investigative Pathology

Ionizing Radiation Accelerates the Development of Atherosclerotic Lesions in ApoE^–/– Mice and Predisposes to an Inflammatory Plaque Phenotype Prone to Hemorrhage

Fiona Anne Stewart^*, Sylvia Heeneman, Johannes te Poele^*, Jacqueline Kruse^*, Nicola S. Russell, Marion Gijbels and Mat Daemen

From the Divisions of Experimental Therapy^* and Radiotherapy, The Netherlands Cancer Institute, Amsterdam; and the Departments of Pathology and Molecular Genetics, University of Maastricht, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands

After radiotherapy treatment, there is an increased incidence of localized atherosclerosis in patients with Hodgkin’s disease, breast cancer, and head and neck cancer. Here, we established a mouse model to study the development and progression of radiation-induced atherosclerosis and to compare the phenotype of these lesions with age-related atherosclerosis. Atherosclerosis-prone ApoE^–/– mice fed a regular chow diet received single radiation doses of 14 Gy or sham treatments (0 Gy) to the neck, including both carotid arteries. At 22, 28, and 34 weeks after irradiation, blood samples were taken, and the arterial tree was removed for histological examination. Cholesterol levels in irradiated mice were not significantly different from age-matched controls, and markers of systemic inflammation (soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, and C-reactive protein) were not elevated. The lesions in irradiated arteries were macrophage rich, with a remarkable influx of inflammatory cells, predominantly granulocytes. Intraplaque hemorrhage and erythrocyte-containing macrophages were seen only in lesions of irradiated arteries. Based on these data, we propose that irradiation accelerates the development of macrophage-rich, inflammatory atherosclerotic lesions prone to intraplaque hemorrhage.

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