Marked oestrus cycle-dependent regulation of rat arterial KV 7.4 channels driven by GPER1.

BACKGROUND AND PURPOSE: Kcnq-encoded KV 7 channels (termed KV 7.1-5) regulate vascular smooth muscle cell (VSMC) contractility at rest and as downstream targets of receptor mediated responses. However, the current literature focuses predominantly on males. Considering the known impact of sex, the oestrus cycle and sex-hormones on vascular reactivity, the aim of this investigation was to characterise the molecular and functional properties of KV 7 within renal and mesenteric arteries from female Wistar rats separated into Di-oestrus and Met-oestrus (F-D/M) and Pro-oestrus and Oestrus (F-P/E). EXPERIMENTAL APPROACH: RT-qPCR, immunocytochemistry, proximity-ligation assay and wire myography were performed in renal and mesenteric arteries. Circulating sex-hormone concentrations was determined by liquid chromatography tandem mass-spectrometry. Whole-cell electrophysiology undertaken on cells expressing KV 7.4 in association with G-protein coupled Oestrogen receptor 1 (GPER1). KEY RESULTS: The KV 7.2-5 activators S-1/ML213 and the pan-KV 7 inhibitor Linopirdine were more effective in arteries from F-D/M compared to F-P/E animals. In VSMCs isolated from F-P/E rats, the membrane abundance of KV 7.4 but not KV 7.1, KV 7.5 and Kcne4 was reduced compared to F-D/M cells. Plasma oestradiol was significantly higher in F-P/E compared to F-D/M and progesterone showed the converse pattern. Oestradiol/GPER1 agonist G-1 diminished KV 7.4 currents in heterologous expression system and reduced KV 7.4 membrane abundance, ML213 relaxations, and interaction between KV 7.4 and the molecular chaperone protein, heat shock protein 90 (HSP90), in arteries from F-D/M but not F-P/E. CONCLUSIONS AND IMPLICATIONS: GPER1 signalling decreases KV 7.4 membrane abundance in conjunction with diminished interaction with HSP90, giving rise to a 'pro-contractile state.