City Research Online

Abstract

Introduction: Kcnq-encoded KV7 channels (termed KV7.1-5) are essential regulators of vascular physiology and are associated with pathophysiological states, however, vascular studies on Kv7 channels to date have focussed almost solely on arteries from males. Considering impact of sex, the oestrus cycle and sex-hormones on vascular reactivity, the aim of this project was to characterise properties of KV7 channels within several arteries from male and female Wistar rats separated into Di-oestrus and Metoestrus (F-D/M) and Pro-oestrus and Oestrus (F-P/E) from normotensive (NT) and spontaneously hypertensive rats (SHRs).

Methods: RT-qPCR, immunocytochemistry and proximity-ligation assay determined KV7 expression and interactions. Wire myography characterised vascular reactivity. Circulating sex-hormone concentrations were determined by Enzyme linked immunosorbent assays (ELISA). Whole-cell electrophysiology determined the specificity of KV7 channel modulators and revealed the effect of Estrogen receptor stimulation on KV7 currents.

Key results: The molecular and functional characteristics of vascular KV7 channels were impaired within arteries from F-P/E compared to F-D/M animals, which corelated with
raised serum Oestradiol E2. Moreover, F-P/E like KV7 characteristics could be replicated in arteries from F-D/M by supplemental Oestradiol E2. Interestingly, KV7 channel function was preserved within female SHRs when compared to males. A novel functional role for KV7.1 was identified within prostacyclin mediated relaxation. Finally, endothelial cells express functional KV7 channels.

Conclusions and implications: This dissertation has revealed dramatic alterations in Kv7 channel role throughout the oestrus cycle. A novel G-protein coupled Oestrogen receptor mediates a post transcriptional decrease in KV7 membrane abundance, giving rise to a ‘pro-contractile state.’ In addition, KV7 channels potentially represent one of the many factors that differentiates the aetiology of hypertension between age-matched men and women. Finally, the contribution of KV7.1 to receptor mediated relaxation and the expression of KV7 within the endothelium adds new layers of complexity to the control of vascular tone by these channels.

Publication Type:	Thesis (Doctoral)
Subjects:	Q Science > Q Science (General) R Medicine > R Medicine (General) R Medicine > RZ Other systems of medicine
Departments:	School of Health & Medical Sciences > Cardiovascular and Genomics Research Institute School of Health & Medical Sciences > School of Health & Medical Sciences Doctoral Theses Doctoral Theses

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