%0 Journal Article
%A Kowalewska, Paulina M
%A Sancho González, María
%A Fabris, Sergio
%A Huff, Murray W
%A Gros, Robert
%A Welsh, Donald G
%T From cells to organism: impact of dyslipidemia on inwardly rectifying K channels and cerebral vascular function.
%D 2025
%U https://hdl.handle.net/20.500.14352/136756
%X Evidence increasingly suggests that dyslipidemia diminishes dilatory function of resistance arteries by altering ion channel activity. Focusing on the cerebral vasculature, this study investigated whether inwardly rectifying K 2.1 (K2.1) channels are targeted early in dyslipidemia. Experiments began at the cellular level (patch-clamp electrophysiology), then progressed to isolated arteries (pressure myography) and whole animals (arterial spin-labeling magnetic resonance imaging). Lipid analysis confirmed dyslipidemia in (normal chow) and C57BL/6 mice fed a high-fat high-cholesterol (HFHC) diet for 8 weeks; no aortic plaques were observed. Patch-clamp electrophysiology revealed a marked reduction in endothelial but not smooth muscle K activity in both dyslipidemic models; this K activity was recoverable by plasma membrane cholesterol depletion. These cellular changes notably diminished flow-induced vasodilation in cerebral arteries isolated from both dyslipidemic models; such deficits were observed in endothelial arteries. A blood pressure challenge induced a perfusion phenotype in HFHC-C57BL/6 but not genetic deletion () mice, consistent with reduced K activity and flow-mediated dilation. Our findings highlight that endothelial K2.1 channels are targeted early in dyslipidemia, which was associated with attenuated flow-mediated dilation in our acute HFHC model. This change likely moderates the range of blood flow control and substrate delivery to active brain tissue.
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