Endothelial SK3 channel-associated ca2+ microdomains modulate blood pressure

Fui C. Yap, David S. Weber, Mark S. Taylor, Mary I. Townsley, Brian S. Comer, James Maylie, John Adelman, Mike T. Lin

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Activation of vascular endothelial small-(KCa2.3, SK3) or intermediate-(KCa3.1, IK1) conductance Ca2+-activated potassium channels induces vasorelaxation via an endothelium-derived hyperpolarization (EDH) pathway. Although the activation of SK3 and IK1 channels converges on EDH, their subcellular effects on signal transduction are different and not completely clear. In this study, a novel endothelium-specific SK3 knockout (SK3−/−) mouse model was utilized to specifically examine the contribution of SK3 channels to mesenteric artery vasorelaxation, endothelial Ca2+ dynamics, and blood pressure. The absence of SK3 expression was confirmed using real-time quantitative PCR and Western blot analysis. Functional studies showed impaired EDH-mediated vasorelaxation in SK3−/− small mesenteric arteries. Immunostaining results from SK3−/− vessels confirmed the absence of SK3 and further showed altered distribution of transient receptor potential channels, type 4 (TRPV4). Electrophysiological recordings showed a lack of SK3 channel activity, while TRPV4-IK1 channel coupling remained intact in SK3−/− endothelial cells. Moreover, Ca2+ imaging studies in SK3−/− endothelium showed increased Ca2+ transients with reduced amplitude and duration under basal conditions. Importantly, SK3−/− endothelium lacked a distinct type of Ca2+ dynamic that is sensitive to TRPV4 activation. Blood pressure measurements showed that the SK3−/− mice were hypertensive, and the blood pressure increase was further enhanced during the 12-h dark cycle when animals are most active. Taken together, our results reveal a previously unappreciated SK3 signaling microdomain that modulates endothelial Ca2+ dynamics, vascular tone, and blood pressure.

Original languageEnglish (US)
Pages (from-to)H1151-H1163
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume310
Issue number9
DOIs
StatePublished - May 1 2016

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Keywords

  • Calcium microdomain
  • Endothelium
  • Intermediateconductance CaCa-activated potassium channel
  • Small conductance CaCa-activated potassium channel
  • Transient receptor potential vanilloid 4

ASJC Scopus subject areas

  • Physiology
  • Medicine(all)
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Yap, F. C., Weber, D. S., Taylor, M. S., Townsley, M. I., Comer, B. S., Maylie, J., Adelman, J., & Lin, M. T. (2016). Endothelial SK3 channel-associated ca2+ microdomains modulate blood pressure. American Journal of Physiology - Heart and Circulatory Physiology, 310(9), H1151-H1163. https://doi.org/10.1152/ajpheart.00787.2015