Kcne4 Deletion Sex-Dependently Alters Vascular Reactivity

Voltage-gated potassium ( Kv) channels formed by Kv7 ( KCNQ) alpha-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 alpha-subunits are often regulated by KCNE subfamily ancillary ( beta) 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 alpha-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. (C) 2016 S. Karger AG, Basel