Abstract
Mesenteric artery endothelium expresses both small (SK3)- and intermediate (IK1)-conductance Ca2+-activated K+ (KCa) channels whose activity modulates vascular tone via endothelium-dependent hyperpolarization (EDH). Two other major endothelium-dependent vasodilation pathways utilize nitric oxide (NO) and prostacyclin (PGI2). To examine how ovariectomy (ovx) affects the basal activity and acetylcholine (ACh)-induced activity of each of these three pathways to vasorelaxation, we used wire myograph and electrophysiological recordings. The results from functional studies using isolated murine mesenteric arteries show that ovx reduces ACh-induced endothelium-dependent vasodilation due to decreased EDH and NO contributions, although the contribution of PGI2 is upregulated. Both endothelial SK3 and IK1 channels are functionally coupled to TRPV4 (transient receptor potential, vanilloid type 4) channels: the activation of TRPV4 channels activates SK3 and IK1 channels, leading to EDH-mediated vascular relaxation. The decreased EDH-mediated vasorelaxation in ovx vessels is due to reduced SK3 channel contribution to the pathway. Further, whole-cell recordings using dispersed endothelial cells also show reduced SK3 current density in ovx endothelial cells. Consequently, activation of TRPV4 channels induces smaller changes in whole-cell current density. Thus, ovariectomy leads to a reduction in endothelial SK3 channel activity thereby reducing the SK3 contribution to EDH vasorelaxation.
Highlights
Vascular endothelial cells provide important regulatory mechanisms to the modulation of vascular tone
Sonkusare et al has recently demonstrated that activating TRPV4 channels induces vasodilation in mesenteric arteries due to Ca2+ influx via these channels that leads to Ca2+-activation of either SK3 or IK1 channels, and activation of the endothelium-dependent hyperpolarization (EDH) pathway [10]
Following either natural menopause or prophylactic surgical removal of ovaries against ovarian cancer, women lose the protective benefits of circulating ovarian hormones, but may develop higher risk factors for diseases compared to agematched women with intact ovaries
Summary
Vascular endothelial cells provide important regulatory mechanisms to the modulation of vascular tone. These endothelial vasoactive factors include both vasoconstrictors and vasodilators, and the contribution of ECs to vascular tone is the net effect of these vasoactive factors. The three major endothelium-dependent vasodilation pathways best characterized are: nitric oxide (NO), prostacyclin (PGI2), and endothelium-dependent hyperpolarization (EDH), with EDH-induced vasorelaxation being the least understood. Each of their contribution to vascular tone may change with physiological conditions, such as menopause, diabetes, and aging [2,3,4]. Sonkusare et al has recently demonstrated that activating TRPV4 (transient receptor potential, vanilloid type 4) channels induces vasodilation in mesenteric arteries due to Ca2+ influx via these channels that leads to Ca2+-activation of either SK3 or IK1 channels, and activation of the EDH pathway [10]
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