Activity of Inwardly Rectifying K + Channels in Cerebral Arteries is Diminished in Dyslipidemia Without Overt Effects on Cerebral Blood Flow

Abstract

Endothelial dysfunction associated with dyslipidemia is a major contributor to cardiovascular disease. Dilatory function of resistance arteries is diminished in dyslipidemia through altered activity of ion channels that set membrane potential. We examined whether inwardly rectifying K+ (KIR) channels are targeted early in dyslipidemia and if alterations impact cerebral blood flow control. Experiments began at the cellular level (patch-clamp electrophysiology) and then were extended to isolated arteries (pressure myography) and whole animals (arterial spin-labelling magnetic resonance imaging). Initial lipid analysis confirmed the dyslipidemic state of LDLR-/- (normal chow) and C57BL/6 mice fed a high-cholesterol high-fat (HFHC) diet for 8 weeks; note aortic plaque formation was absent in these animal models. Patch-clamp electrophysiology revealed a marked reduction in endothelial but not smooth muscle KIR activity in both dyslipidemic models. Flow activation of KIR was also reduced in endothelial cells from LDLR-/- and HFHC mice. However, endothelial KIR activity was recovered in dyslipidemic mice by depleting the plasma membrane of cholesterol. Consistent with these cellular changes, we observed diminished shear-induced vasodilation in cerebral arteries isolated from dyslipidemic animals. However, these cellular and tissue level changes did not alter cerebral blood flow at baseline or in response to a blood pressure challenge (phenylephrine injection through a peritoneal catheter, 0.816 mg/kg). The maintenance of blood flow control was observed across a full range of structures including the cortex, cerebral nuclei, hippocampus, thalamus, hypothalamus and midbrain. Our findings highlight that while KIR channel function is targeted early on in dyslipidemia, compensatory mechanisms can maintain brain blood flow to preserve neurological function.