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Regulation of VCAM‐1 expression by TNF‐α in cerebral arteries of control and diabetic mice

Diabetic patients suffer from micro‐ and macroangiopathy. Previous studies show that plasma levels of the pro‐inflammatory cytokine TNF‐α are elevated in diabetic patients and that this cytokine promotes atherosclerosis, but the role of TNF‐α in the development of diabetic microangiopathy is unclear. Upregulation of the cell adhesion molecule VCAM‐1 is one of the earliest detectable responses to vascular disease. Here we investigate the impact of TNF‐α signaling on VCAM‐1 expression in small resistance arteries (10 to 250 μm) from WT, Apoe−/−, TNF‐α−/− and Apoe−/−/TNF‐α−/− mice, under normal or diabetic conditions. Using confocal immunofluorescence microscopy, we show that VCAM‐1 is expressed in both endothelial and smooth muscle cells and that higher expression levels correlate to larger caliber vessels. Loss of TNF‐α resulted in decreased VCAM‐1 expression, whereas loss of TNF‐α on an Apoe−/− background had no effect. Contrary to expectations, arteries from Apoe−/− did not show higher VCAM‐1 levels than those of WT mice. Interestingly, only arteries from mice lacking TNF‐α responded with increased VCAM‐1 expression when the animals became diabetic. These results suggest that TNF‐α may regulate VCAM‐1 expression in small arteries under basal conditions, but not under diabetic conditions. Supported by: Swedish Heart & Lung Foundations, Research Medical Council & Royal Physiographic Society in Lund