Sexual dimorphism in prostacyclin‐mimetic responses within rat mesenteric arteries: A novel role for K_V7.1 in shaping IP receptor‐mediated relaxation

Abstract

Background and Purpose Prostacyclin mimetics express potent vasoactive effects via prostanoid receptors that are not unequivocally defined, as to date no study has considered sex as a factor. The aim of this study was to determine the contribution of IP and EP3 prostanoid receptors to prostacyclin mimetic iloprost‐mediated responses, whether KV7.1–5 channels represent downstream targets of selective prostacyclin‐IP‐receptor agonist MRE‐269 and the impact of the oestrus cycle on vascular reactivity. Experimental Approach Within second‐order mesenteric arteries from male and female Wistar rats, we determined (1) relative mRNA transcripts for EP1–4 (Ptger1–4), IP (Ptgi) and TXA2 (Tbxa) prostanoid receptors via RT‐qPCR; (2) the effect of iloprost, MRE‐269, isoprenaline and ML277 on precontracted arterial tone in the presence of inhibitors of prostanoid receptors, potassium channels and the molecular interference of KV7.1 via wire‐myograph; (3) oestrus cycle stage via histological changes in cervical cell preparations. Key Results Iloprost evoked a biphasic response in male mesenteric arteries, at concentrations ≤100 nmol·L−1 relaxing, then contracting the vessel at concentration ≥300 nmol·L−1, a process attributed to IP and EP3 receptors respectively. Secondary contraction was absent in the females, which was associated with a reduction in Ptger3. Pharmacological inhibition and molecular interference of KV7.1 significantly attenuated relaxations produced by the selective IP receptor agonist MRE‐269 in male and female Wistar in dioestrus/metoestrus, but not pro‐oestrus/oestrus. Conclusions and Implications Stark sexual dimorphisms in iloprost‐mediated vasoactive responses are present within mesenteric arteries. KV7.1 is implicated in IP receptor‐mediated vasorelaxation and is impaired by the oestrus cycle.

Cycling matters: Sex hormone regulation of vascular potassium channels

“…*= hormone mediator speculated. Channel function/expression Upregulated Downregulated No effect Ion channel Hormone Subtype Model Ref Subtype Model Ref Subtype Model Ref K V 7 Estrogen K V 7.1 Xenopus Oocytes [ 37 ] HT29cl.19A [ 38 ] Rat: Distal colic crypt cells [ 38–40 ] K V 7.1: KCNE1 Mouse/Guinea pig: Ventricular myocytes [ 41 ] K V 7.1: KCNE3 Chinese Hamster Ovarian cells [ 40 ] K V 7.4 Rat mesenteric/renal VSMC [ 12 , …”

“…Pan-K V 7 blockers and molecular knockdown of K V 7.4/K V 7.5 channels also impair receptor-mediated vasorelaxation generated by β-adrenoreceptor, adenosine, calcitonin-gene related peptide, and prostacyclin (IP) receptor agonists (cAMP-linked [ 12 , 96 , 104 , 109 , 110 ]), as well as atrial natriuretic peptide and nitric oxide-mediated responses (cGMP-linked [ 111–113 ]) in many arteries from male rats. Interestingly, β-adrenoreceptor mediated relaxation differentially couples to K V 7 in a vascular bed specific manner, via PKA in renal arteries, and a novel alternate signaling cascade mediated by exchange protein activated by cAMP (EPAC) in mesenteric arteries [ 109 ].…”

“…Further, Berg (2018) observed that vascular K V 7 channel function was preserved in female hypertensive animals when compared to males [ 114 ]. As above, Baldwin et al (2022) demonstrated a novel role for K V 7.1 as the downstream target of IP receptor evoked relaxation in mesenteric arteries from both male and female rats [ 12 ]. However, the sensitivity of IP receptor-mediated relaxation to inhibition of K V 7.1 by pre-incubation of HMR-1556 (10 µmol-L −1 ) was absent in arteries from animals harvested during proestrus or estrus stages of the estrus cycle [ 12 ], stages associated with an initial spike in serum concentration of E2 [ 17 ].…”

“…Yet, comparably little is known about the influence of sex hormones on vascular smooth muscle K + channels. Recently, Baldwin et al 2022 and 2023 showed the functional impact of arterial KCNQ-encoded voltage-dependent potassium channels (termed Kv7s) changed considerably across the rat estrus cycle [ 12 , 15 ]. These works are in the vanguard of research identifying estrus-cycle-dependent oscillations in smooth muscle functionality outside of the sex-dependent differences in arterial responsiveness conventionally reported [ 16 ].…”

Skin Microhemodynamics and Mechanisms of Its Regulation in Type 2 Diabetes Mellitus

“…Ion channels and membrane receptors participate in the regulation of vasoactivity: large-conductance Ca 2+ -activated K + -channel, voltage-dependent K + -channel, mechanosensitive ion channels, receptors-ion channels (purine, isoforms of transient receptor potential channel, nicotinic acetylcholine receptors), receptors coupled to heterotrimeric GTPbinding proteins (adrenoceptors, adenosine, serotonin, vasopressin, endothelin receptors and other), receptors-tyrosine kinases (insulin receptor, Tie1-2, growth factor receptors) [140][141][142], receptor-type protein tyrosine phosphatases [143][144][145]. The following signal transduction sequences can serve as examples of principle schemes of intracellular and intercellular communication components activation in the action of vasoactive factors: (1) phospholipase A2 → cytochrome P450 → eicosanoids → large-conductance Ca 2+ -activated K + -channel, the activation of which leads to hyperpolarization of the membrane of smooth muscle cells and subsequent relaxation of the vessel (for example, in shear stress); (2) endothelial NO-synthase → NO release → smooth muscle cells → soluble guanylate cyclase → cGMP → protein kinase G → change of Ca 2+ concentration in the cytosol → large-conductance Ca 2+ -activated K + -channel; (3) oxidases (NADPH-oxidase, xanthine oxidase and others) → reactive oxygen species (ROS) → decreased NO and/or increased hydrogen peroxide levels.…”