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Science 336 (6081): 597-601

Copyright © 2012 by the American Association for the Advancement of Science

Elementary Ca2+ Signals Through Endothelial TRPV4 Channels Regulate Vascular Function

Swapnil K. Sonkusare,1 Adrian D. Bonev,1 Jonathan Ledoux,1,2 Wolfgang Liedtke,3 Michael I. Kotlikoff,4 Thomas J. Heppner,1 David C. Hill-Eubanks,1 Mark T. Nelson1,5,*

Abstract: Major features of the transcellular signaling mechanism responsible for endothelium-dependent regulation of vascular smooth muscle tone are unresolved. We identified local calcium (Ca2+) signals ("sparklets") in the vascular endothelium of resistance arteries that represent Ca2+ influx through single TRPV4 cation channels. Gating of individual TRPV4 channels within a four-channel cluster was cooperative, with activation of as few as three channels per cell causing maximal dilation through activation of endothelial cell intermediate (IK)- and small (SK)-conductance, Ca2+-sensitive potassium (K+) channels. Endothelial-dependent muscarinic receptor signaling also acted largely through TRPV4 sparklet-mediated stimulation of IK and SK channels to promote vasodilation. These results support the concept that Ca2+ influx through single TRPV4 channels is leveraged by the amplifier effect of cooperative channel gating and the high Ca2+ sensitivity of IK and SK channels to cause vasodilation.

1 Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT 05405, USA.
2 Research Center, Montreal Heart Institute, and Department of Medicine, Université de Montréal, Montreal, QC H1T 1C8, Canada.
3 Department of Medicine and Neurobiology, and Center for Translational Neuroscience, Duke University Medical Center, Durham, NC 27710, USA.
4 Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
5 Institute of Cardiovascular Sciences, University of Manchester, Manchester M13 9NT, UK.

* To whom correspondence should be addressed. E-mail: mark.nelson{at}uvm.edu


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