Endothelial K2 channel dysfunction in aged cerebral parenchymal arterioles.

Aging is associated with cognitive decline incompletely understood mechanisms. Cerebral microvascular dysfunction occurs in aging, particularly impaired endothelium-mediated dilation. Parenchymal arterioles are bottlenecks of the cerebral microcirculation, and dysfunction causes a mismatch in nutrient demand and delivery, leaving neurons at risk. Extracellular nucleotides elicit parenchymal arteriole dilation by activating endothelial purinergic receptors (P2Y), leading to opening of K channels, including inwardly-rectifying K channels (K2). These channels amplify hyperpolarizing signals, resulting in dilation. However, it remains unknown if endothelial P2Y and K2 signaling are altered in brain parenchymal arterioles during aging. We hypothesized that aging impairs endothelial P2Y and K2 function in parenchymal arterioles. We observed reduced dilation to the purinergic agonist 2-methyl-S-ADP (1 µM) in arterioles from Aged (>24-month-old) mice when compared to Young (4-6 months of age) despite similar hyperpolarization in endothelial cells tubes. No differences were observed in vasodilation or endothelial cell hyperpolarization to activation of small- and intermediate-conductance Ca-activated K channels (K2.3 / K3.1) by NS309. Hyperpolarization to 15 mM [K] was smaller in Aged than Young mice, despite a paradoxical increased dilation in Aged arterioles to 15 mM [K] that was unchanged by endothelium removal. K2 Inhibition attenuated vasodilatory responses to 15 mM [K] and 1 µM 2-me-S-ADP in both Young and Aged arterioles. Further, we observed a significant increase in myogenic tone in Aged parenchymal arterioles, which was not enhanced by endothelium removal. We conclude that aging impairs endothelial K2 channel function in the cerebral microcirculation with possible compensation by smooth muscle cells.