Abstract
LDL receptor-null mice on a Western diet (WD) have inflammation in large arteries and endothelial dysfunction in small arteries, which are improved with the apolipoprotein A-I mimetic D-4F. The role of hyperlipidemia in causing inflammation of very small vessels such as brain arterioles has not previously been studied. A WD caused a marked increase in the percent of brain arterioles with associated macrophages (microglia) (P < 0.01), which was reduced by oral D-4F but not by scrambled D-4F (ScD-4F; P < 0.01). D-4F (but not ScD-4F) reduced the percent of brain arterioles associated with CCL3/macrophage inflammatory protein-1alpha (P < 0.01) and CCL2/monocyte chemoattractant protein-1 (P < 0.001). A WD increased (P < 0.001) brain arteriole wall thickness and smooth muscle alpha-actin, which was reduced by D-4F but not by ScD-4F (P < 0.0001). There was no difference in plasma lipid levels, blood pressure, or arteriole lumen diameter with D-4F treatment. Cognitive performance in the T-maze continuous alternation task and in the Morris Water Maze was impaired by a WD and was significantly improved with D-4F but not ScD-4F (P < 0.05). We conclude that a WD induces brain arteriole inflammation and cognitive impairment that is ameliorated by oral D-4F without altering plasma lipids, blood pressure, or arteriole lumen size.
Highlights
LDL receptor-null mice on a Western diet (WD) have inflammation in large arteries and endothelial dysfunction in small arteries, which are improved with the apolipoprotein A-I mimetic D-4F
We report here that feeding a WD to LDL receptor-null (LDLR2/2) mice induced brain arteriole inflammation and cognitive impairment, which were ameliorated by oral D-4F without altering plasma lipids, blood pressure, or arteriole lumen size
All of the microglia associated with arterioles were on the adventitial side of the vessel, but electron microscopy revealed that many were within the vessel wall as defined as being within the basal lamina
Summary
LDL receptor-null mice on a Western diet (WD) have inflammation in large arteries and endothelial dysfunction in small arteries, which are improved with the apolipoprotein A-I mimetic D-4F. The role of hyperlipidemia in causing inflammation of very small vessels such as brain arterioles has not previously been studied. A WD caused a marked increase in the percent of brain arterioles with associated macrophages (microglia) (P , 0.01), which was reduced by oral D-4F but not by scrambled D-4F (ScD-4F; P , 0.01). A WD increased (P , 0.001) brain arteriole wall thickness and smooth muscle a-actin, which was reduced by D-4F but not by ScD-4F (P , 0.0001). The facialis artery studied by Ou et al [3] has a lumen diameter of 180–280 mm, and there is no evidence to suggest that macrophages accumulate in the subendothelial space of such small arteries. It is not likely that macrophages could accumulate between the monolayer of luminal endothelial cells and the smooth muscle cell layer that surrounds them without obstructing the lumen
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