title: 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.
authors.affiliation: Bioelectricity Laboratory, Departments of Pharmacology and Physiology and Biophysics, School of Medicine, University of California, Irvine, Calif., USA.
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Abbott
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Jepps
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D051656:KCNQ Potassium Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism; D008729:Methoxamine / Q000494:pharmacology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D010641:Phenotype; D024642:Potassium Channels, Voltage-Gated / Q000172:deficiency* / Q000235:genetics; D012737:Sex Factors; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D000813:Anilides; D001643:Bridged Bicyclo Compounds; C470587:KCNE4 protein, mouse; D051656:KCNQ Potassium Channels; C506326:KCNQ5 channel, mouse; C492167:Kcnq4 protein, mouse; C000591918:N-mesitybicyclo(2.2.1)heptane-2-carboxamide; D024642:Potassium Channels, Voltage-Gated; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D008729:Methoxamine