Glucocorticoid administration reduces neointimal proliferation but exacerbates atherogenesis in mice

Low L.*, Kirkby, N.S., Seckl J.R., Walker B.R. and Hadoke P.W.F. Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Scotland, UK.

The influence of glucocorticoids (GCs) on vascular lesion formation, although well-documented, is poorly understood. GC administration reduces neointimal proliferation and atherosclerosis in some animal models but is associated with increased cardiovascular disease in patients. This study addressed the hypothesis that exogenous and endogenous GCs glucocorticoids inhibit atherosclerotic and neointimal lesion development in mice.

Male C57Bl/6J (age 10-12 weeks) and ApoE-/- (5 weeks) mice underwent adrenalectomy (Adx) or sham surgery (n=8/group). Adx mice received either vehicle or dexamethasone (dex; 0.8 or 0.1mg/kg/day) orally in 0.9% saline. One week following Adx all C57Bl/6J mice were subjected to wire injury of the femoral artery and maintained for a further three weeks. In contrast, Apo-/- mice were placed on a high (0.2%) cholesterol Western diet for 12 weeks. At the end of these respective periods mice were killed for isolation of the femoral artery (C57Bl/6J) or aortic arch (ApoE-/-). Neointimal development was assessed in femoral arteries using standard histology whereas atherogenesis was assessed in ApoE-/- using optical projection tomography (OPT).

Adx had no effect on neointimal or atherosclerotic lesion size. In C57Bl/6J mice, dex caused a dose-dependent reduction in body weight (p<0.01) whilst neointimal lesion size (39328±2) was reduced (p<0.05) by high (8056±3430μmspan class="super">2), but not by low (46699±6964μm2), dose dex. High dose dex, however, was also associated with thrombotic occlusion at the site of injury. In ApoE-/- mice, dex reduced body weight (p<0.005) and significantly increased (p<0.05) lesion volume (2.70+0.20x108μm3), compared with sham (1.89+0.19x108μm3), in the brachiocephalic trunk.

These results demonstrate the complex influence of GCs on lesion development. Removal of endogenous GC did not alter lesion size, suggesting a limited role in regulation of neointimal development and atherosclerosis. In contrast, the influence of exogenous GCs on vascular remodelling was dependent upon the nature of lesion under investigation, as well as dose. These results suggest that GC administration may be beneficial in fibro-proliferative remodelling but detrimental in atherosclerosis.