Abstract 4369129: Essential Role of KCNQ5 (Kv7.5) Potassium Channels in Vascular Reactivity and Adrenergic Signaling

Abstract

Introduction/Background: Vascular tone dysregulation is central to cardiovascular pathophysiology. KCNQ (Kv7) potassium channels, primarily heteromeric KCNQ4/5 channels, regulate smooth muscle membrane potential and contractility, yet the specific role of the KCNQ5 subunit in vascular reactivity remains underexplored. The absence of KCNQ5-specific tools has limited mechanistic understanding, particularly regarding receptor-mediated signaling in distinct vascular beds. Research Questions/Hypothesis: We hypothesized that KCNQ5 plays a critical, region-specific role in vascular contractility and receptor-mediated relaxation, particularly to adrenergic stimuli. We aimed to determine whether genetic deletion of KCNQ5 disrupts vasoreactivity and arterial signaling dynamics. Methods/Approach: We generated a CRISPR-based germline KCNQ5 knockout ( Kcnq5 -/- ) rat line. Using in vivo multimodal monitoring (cardiac and brain hemodynamics), ex vivo myography of mesenteric and cerebral arteries, and in vitro electrophysiology of Xenopus oocytes expressing KCNQ4/5/KCNE4 complexes, we analyzed vascular responses to pharmacologic and physiologic stimuli including adrenergic agonists, KCNQ modulators, and the botanical KCNQ5 isoform-selective vasorelaxant aloperine. Results/Data: Kcnq5 -/- rats displayed blunted heart rate, cerebral blood flow, and vasoregulatory responses to hypercapnia and isoflurane, and impaired cerebral vasodilation to aloperine. In contrast, cerebral artery segments mounted in a wire myograph displayed preserved function. In mesenteric artery segments studied using wire myography, deletion of KCNQ5 did not affect basal tone or luminal diameter but impaired relaxation responses to the Kv7 channel opener ML213, aloperine, and the β-adrenergic agonist isoprenaline. Constriction to the α 1 -adrenergic agonist methoxamine was enhanced and showed reduced sensitivity to linopirdine, highlighting KCNQ5’s key role in regulating adrenergic vasoconstriction. Cellular electrophysiology studies delineated PKA/PKC sensitivity of KCNQ5-containing channels. Conclusions: KCNQ5 is essential for receptor-mediated signaling in specific vascular beds. Its deletion enhances α 1 -adrenergic constriction and impairs β-adrenergic and botanical-induced vasorelaxation, highlighting its important functional role. These findings identify KCNQ5 as a key component of Kv7 channel architecture and vasoregulation, which likely varies across vascular beds.