Atherosclerosis differentially affects calcium signalling in endothelial cells from aortic arch and thoracic aorta in Apolipoprotein E knockout mice

Abstract

Apolipoprotein‐E knockout (ApoE ^−/−) mice develop hypercholesterolemia and are a useful model of atherosclerosis. Hypercholesterolemia alters intracellular Ca ²⁺ signalling in vascular endothelial cells but our understanding of these changes, especially in the early stages of the disease process, is limited. We therefore determined whether carbachol‐mediated endothelial Ca ²⁺ signals differ in plaque‐prone aortic arch compared to plaque‐resistant thoracic aorta, of wild‐type and ApoE ^−/− mice, and how this is affected by age and the presence of hypercholesterolemia. The extent of plaque development was determined using en‐face staining with Sudan IV. Tissues were obtained from wild‐type and ApoE ^−/− mice at 10 weeks (pre‐plaques) and 24 weeks (established plaques). We found that even before development of plaques, significantly increased Ca ²⁺ responses were observed in arch endothelial cells. Even with aging and plaque formation, ApoE ^−/− thoracic responses were little changed, however a significantly enhanced Ca ²⁺ response was observed in arch, both adjacent to and away from lesions. In wild‐type mice of any age, 1–2% of cells had oscillatory Ca ²⁺ responses. In young ApoE ^−/− and plaque‐free regions of older ApoE ^−/−, this is unchanged. However a significant increase in oscillations (~13–15%) occurred in thoracic and arch cells adjacent to lesions in older mice. Our data suggest that Ca ²⁺ signals in endothelial cells show specific changes both before and with plaque formation, that these changes are greatest in plaque‐prone aortic arch cells, and that these changes will contribute to the reported deterioration of endothelium in atherosclerosis.

Abstract

We have investigated aortic endothelial cell calcium signalling changes in the Apolipoprotein E knockout mouse model of atherosclerosis. Our data show that calcium signals in endothelial cells undergo specific changes both before and with plaque formation, that these changes are greater in plaque‐prone aortic arch than in plaque‐resistant thoracic aorta, and that these changes will contribute to the reported deterioration of endothelium in atherosclerosis.