Kcne4 Deletion Sex-Dependently Alters Vascular Reactivity

Abstract

Voltage-gated potassium (Kv) channels formed by Kv7 (KCNQ) α-subunits are recognized as crucial for vascular smooth muscle function, in addition to their established roles in the heart (Kv7.1) and the brain (Kv7.2-5). In vivo, Kv7 α-subunits are often regulated by KCNE subfamily ancillary (β) subunits. We investigated the effects of targeted germline Kcne4 deletion on mesenteric artery reactivity in adult male and female mice. Kcne4 deletion increased mesenteric artery contractility in response to α-adrenoceptor agonist methoxamine, and decreased responses to Kv7.2-7.5 channel activator ML213, in male but not female mice. In contrast, Kcne4 deletion markedly decreased vasorelaxation in response to isoprenaline in both male and female mice. Kcne4 expression was 2-fold lower in the female versus the male mouse mesenteric artery, and Kcne4 deletion elicited only moderate changes of other Kcne transcripts, with no striking sex-specific differences. However, Kv7.4 protein expression in females was twice that in males, and was reduced in both sexes by Kcne4 deletion. Our findings confirm a crucial role for KCNE4 in regulation of Kv7 channel activity to modulate vascular tone, and provide the first known molecular mechanism for sex-specificity of this modulation that has important implications for vascular reactivity and may underlie sex-specific susceptibility to cardiovascular diseases.

4‐Aminopyridine: a pan voltage‐gated potassium channel inhibitor that enhances Kv7.4 currents and inhibits noradrenaline‐mediated contraction of rat mesenteric small arteries

“…In this study, we also observed a small contraction with 5 mM 4‐AP consistent with its effect to inhibit delayed rectifier K v currents. Given the still somewhat unknown and varied K v 7 channel subtype expression, channel stoichiometry across vascular beds (Jepps et al, ) and coassembly with β‐subunits (Jepps et al, ; Abbott and Jepps, ), it is possible that 4‐AP is less able to relax other arteries that are more dependent on K v 1, K v 2 or K v 7.5 activities, instead inducing a contractile response at concentrations >1 mM. We suggest that the complexity of different native systems together with the multifarious nature of 4‐AP, particularly at higher concentrations, is responsible for any discrepancies with previous studies.…”

Negative feedback regulation of vasocontraction by potassium channels in 10‐ to 15‐day‐old rats: Dominating role of Kv7 channels

“…(a) The data have been obtained from male animals only. Thus, sex as a biological variable was not considered, while the function of potassium channels in the vasculature can be sex‐dependent . However, it was the aim of our study to present a comprehensive investigation of the negative feedback regulation of vasocontraction by various types of potassium channels in early postnatal ontogenesis.…”

Deletion in mice of X‐linked, Brugada syndrome–and atrial fibrillation–associatedKcne5augments ventricular Kvcurrents and predisposes to ventricular arrhythmia

“…To aid in this endeavor, we studied the effects of germline deletion of Kcne5 in mice. Transgenic mouse models have been instrumental in detecting and characterizing novel native functions of KCNE subunits (23,25,30,(37)(38)(39)(40)(41)(42)(43)(44)(45). By phenotypically studying Kcne5 -/0 mice, we discovered that Kcne5 regulates K V 2.1 current (I K,slow,2 ) (27,29) in mouse ventricles.…”