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.

Interleukin 6 (IL‐6) is a circulating cytokine implicated in inflammatory processes. However, the broad effects of IL‐6 receptor (IL‐6R) signalling on other circulating cytokines is not known. Using summary‐level data from genome‐wide association studies, we leveraged genetic variants that proxy IL‐6R signalling in two‐sample Mendelian randomization analyses to investigate effects on levels of 40 circulating cytokines. Increased genetically proxied IL‐6R signalling was associated with reduced levels of 10 circulating interleukins, chemokines and growth factors. The significant results include IL‐10 (Mendelian randomization estimate −0.306, standard error [SE] 0.093), IL‐4 (estimate −0.393, SE 0.1007), eotaxin (estimate −0.510, SE 0.1213) and Fibroblast growth factor (estimate −0.334, SE 0.1005). The findings from this study support the feedback effects of IL‐6R signalling on reducing levels of some circulating cytokines and identify compensatory mechanisms that maybe modulating its inflammatory effects. These results provide insight into the mechanisms by which IL‐6R signalling may be contributing to inflammatory and autoimmune diseases.

Background and purpose- Prostacyclin mimetics are widely used clinically. As such it is pertinent to understand the mechanisms underlying the vasoactive response to such agents, yet to date, no study has considered sex as a factor. The aim of this study was to characterise the effect of prostacyclin mimetics, Iloprost and MRE-269, on precontracted arterial tone from male and female Wistar arteries. As a secondary consideration, we investigated Kcnq-encoded KV7 channels as potential downstream targets of prostacyclin-IP-receptor mediated signalling. Experimental approach- Relative mRNA transcript and protein abundance were determined by RT-qPCR and immunocytochemistry respectively. The effect of Iloprost and MRE-269 was determined on pre-contracted arterial tone in the presence of pharmacological modulators of potassium channels and molecular interreference of KV7.1 within 2nd order mesenteric and left anterior descending arteries from male and female Wistar rats. Key results- Iloprost evoked a bi-phasic response in male mesenteric arteries, at low concentrations relaxing, then contracting the vessel at high concentration in a process attributed to IP and EP3 receptors respectively. Secondary contraction was absent in the females, potentially underpinned by a reduction in Ptger3. Pharmacological inhibition and molecular interference of KV7.1 significantly attenuated MRE-269 mediated relaxation in male and female Wistar in Diestrus / Metoestrous, 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.

Interleukin 6 (IL-6) is a circulating cytokine that is implicated in a range of inflammatory diseases. However, the broad effects of IL-6 receptor (IL-6R) signalling on other circulating cytokines is not known. Using summary-level data from genome-wide association studies, we leveraged genetic variants that proxy IL-6R signalling in two-sample Mendelian randomization analyses to investigate effects on levels of 40 circulating cytokines. Increased genetically proxied IL-6R signalling was associated with reduced levels of 10 circulating interleukins, chemokines, and growth factors. The findings from this study support feedback effects of IL-6R signalling on reducing levels of a range of circulating cytokines and identify compensatory mechanisms that may be modulating its inflammatory effects. These results provide novel insight into the mechanisms by which IL-6R signalling may be contributing to inflammatory and autoimmune diseases.