Analysis Of Radiotherapy Induced Vascular Lesions Reveals Potential Therapies Against Innate Inflammation In An Apoe Knockout Mouse Model

Clinical studies show an increase risk for cardiovascular disease (CVD) at the site of irradiation years after exposure. Radiotherapy together with other cancer therapies contributes to a growing population of cancer survivors in risk of developing radiotherapy induced vascular disease. However, traditional treatments for CVD such as thrombolytic inhibitors and lipid lowering drugs (statins) seem to have no effect on radiation induced vascular disease in mouse models. We have previously demonstrated a sustained chronic inflammation by NF-kB activation in irradiated human arteries. To further investigate radiation induced vascular disease and potential therapies against innate inflammation, we established a mouse model of local irradiation in an atherosclerotic prone ApoE-/- background. ApoE-/- mice fed chow diet were exposed to a single dose of 0 Gy (sham/controls) or 14 Gy at the upper chest and neck area and harvested 10 weeks later. Plasma, thoracic aorta, aortic arch, heart were retrieved and taken for plasma, blood count, en face, mRNA, immunohistochemistry and immunofluorescence analysis. Irradiated mice presented higher total plasma cholesterol levels than controls. En face analysis of aortic arches showed a decreased percentage of lesion size in irradiated arteries compared to controls. However, an increase of MHC class II (IA-b) staining in irradiated aortic roots suggested an induction of inflammation in the context of radiotherapy. These data were supported by the quantification of monocyte chemotactic protein 1 mRNA expression in the thoracic aorta showing a significant increase in irradiated animals compared to unirradiated (p≤0,001). The current data demonstrated that radiotherapy induces a macrophage-rich and inflamed plaque that may explain the increased risk of developing severe clinical events i.e. myocardial infarction or stroke. Further analyses of this partial irradiation mouse model are on-going to assess the potential therapeutic targets involved in innate immunity and NF-kB activation. Results of currently performed therapeutic experiments will be further presented.