Aging Impairs Electrical Conduction Along Endothelium of Resistance Arteries Through Enhanced Ca2+-Activated K ⁺ Channel Activation

Abstract

Objective Intercellular conduction of electrical signals underlies spreading vasodilation of resistance arteries. Small and intermediate-conductance Ca2+ activated K+ channels (SKCa/IKCa) of endothelial cells serve a dual function by initiating hyperpolarization and modulating electrical conduction. We tested the hypothesis that the regulation of electrical signaling by SKCa/IKCa is altered with advancing age. Approach and Results Intact endothelial tubes (60 μm wide; 1-3 mm long) were freshly isolated from male C57BL/6 mouse (Young: 4-6 months; Intermediate: 12-14 months; Old: 24-26 months) superior epigastric arteries. Using dual intracellular microelectrodes, current was injected (±0.1-3 nA) at site 1 while recording membrane potential (Vm) at site 2 (separation distance: 50-2000 μm). Across age groups, greatest differences were observed between Young and Old. Resting Vm in Old (−38±1 mV) was more negative (P<0.05) than Young (−30±1 mV). Maximal hyperpolarization to both direct (NS309) and indirect (acetylcholine) activation of SKCa/IKCa was sustained (ΔVm ~ −40 mV) with age. The length constant (λ) for electrical conduction was reduced (P<0.05) from 1630±80 µm (Young) to 1320±80 μm (Old). Inhibiting SKCa/IKCa with apamin + charybdotoxin or scavenging H2O2 with catalase improved electrical conduction (P<0.05) in Old. Exogenous H2O2 (200 μM) in Young evoked hyperpolarization and impaired electrical conduction; these effects were blocked by apamin + charybdotoxin. Conclusions Enhanced current loss through KCa activation impairs electrical conduction along the endothelium of resistance arteries with aging. Attenuating the spatial domain of electrical signaling will restrict the spread of vasodilation and thereby contribute to blood flow limitations associated with advanced age.

Aging increases capacitance and spontaneous transient outward current amplitude of smooth muscle cells from murine superior epigastric arteries

“…Increased SMC capacitance also would be expected to attenuate the transmission of electrical signals along the vessel and contribute to impairment of conducted (ascending) vasodilation of feed arteries (19). Longitudinal signaling can be further impaired by greater current leakage along the endothelium, as recently shown in endothelial tubes prepared from SEAs from the same strain of mouse studied here (3,4). Functionally, impairing the ability of vasodilation to spread along and among branches of the resistance vasculature can explain how blood flow to exercising muscle is restricted with aging (12,19,42).…”

“…Aging has been shown to increase the function of K Ca channels expressed in endothelial cells isolated from SEAs, an age-related effect that was eliminated by exposure of the cells to polyethylene glycol-conjugated (PEG) catalase (4). Therefore, we also assessed the effects of PEG-catalase (500 U/ml) on SMC whole-cell currents between Ϫ90 and ϩ60 mV, as well as STOC amplitude and frequency assessed at ϩ30 mV.…”

“…However, as shown in resistance networks of the mouse and hamster cremaster muscles, the regulation of BK Ca in arterioles differs from that in feed arteries (49,50), and it is unknown how aging affects BK Ca function in SMCs of skeletal muscle feed arteries. A recent study of endothelial tubes freshly isolated from murine superior epigastric arteries (SEAs) suggests that aging increased the function of endothelial K Ca (4). Therefore, in the present study, we tested the hypothesis that aging would alter BK Ca expression and/or function in SMCs of SEAs, feed arteries that supply skeletal muscles of the anterior abdominal wall, by using patch clamp electrophysiology on freshly isolated SMCs and pressure myography of isolated SEAs.…”

Age-related impairment of conducted dilation in human coronary arterioles

“…Behringer et al (2) have shown that aging impairs electrical conduction along endothelial cell tubes obtained from resistance arteries of the 24-to 26-mo-old mice. In old (19 to 20 mo) mice, Bearden et al (1) found that conducted vasodilation is reduced in the skeletal muscle microcirculation, in vivo, compared with younger (12-14 mo) mice.…”

K Ca 3.1 upregulation preserves endothelium‐dependent vasorelaxation during aging and oxidative stress

“…Our results clearly showed that H 2 O 2 affected endothelial function by increasing K Ca 3.1 expression. As consistent with previous evidence in intact microvascular endothelial tubes (Behringer et al ., 2013), H 2 O 2 activated K Ca 3.1 currents in aortic ECs (Choi et al ., 2013b). Endothelial dysfunction, which was manifested in the form of diminished NO bioavailability, was well compensated for by an increased expression of K Ca 3.1 protein, as shown in aged wild‐type, CerS2 null, and catalase −/− /GPX1 −/− mice, and an upregulation of K Ca 3.1 channel activity.…”