Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

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

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Arachidonic Acid-Induced Dilation in Human Coronary Arterioles: Convergence of Signaling Mechanisms on Endothelial TRPV4-Mediated Ca2+ Entry.
X. Zheng, N. S. Zinkevich, D. Gebremedhin, K. M. Gauthier, Y. Nishijima, J. Fang, D. A. Wilcox, W. B. Campbell, D. D. Gutterman, and D. X. Zhang (2013)
JAHA 2, e000080
   Abstract »    Full Text »    PDF »
Role of impaired endothelial cell Ca2+ signaling in uteroplacental vascular dysfunction during diabetic rat pregnancy.
N. I. Gokina, A. D. Bonev, A. P. Gokin, and G. Goloman (2013)
Am J Physiol Heart Circ Physiol 304, H935-H945
   Abstract »    Full Text »    PDF »
Ageing alters perivascular nerve function of mouse mesenteric arteries in vivo.
E. B. Westcott and S. S. Segal (2013)
J. Physiol. 591, 1251-1263
   Abstract »    Full Text »    PDF »
Partial opening and subconductance gating of mechanosensitive ion channels in dystrophic skeletal muscle.
I. Vasquez, N. Tan, M. Boonyasampant, K. A. Koppitch, and J. B. Lansman (2012)
J. Physiol. 590, 6167-6185
   Abstract »    Full Text »    PDF »
Low intravascular pressure activates endothelial cell TRPV4 channels, local Ca2+ events, and IKCa channels, reducing arteriolar tone.
P. Bagher, T. Beleznai, Y. Kansui, R. Mitchell, C. J. Garland, and K. A. Dora (2012)
PNAS 109, 18174-18179
   Abstract »    Full Text »    PDF »
Optical Recording Reveals Novel Properties of GSK1016790A-Induced Vanilloid Transient Receptor Potential Channel TRPV4 Activity in Primary Human Endothelial Cells.
M. N. Sullivan, M. Francis, N. L. Pitts, M. S. Taylor, and S. Earley (2012)
Mol. Pharmacol. 82, 464-472
   Abstract »    Full Text »    PDF »
Does TRPC3 macrodominate the myoendothelial gap junction microdomain?.
P. I. Aaronson (2012)
Cardiovasc Res 95, 399-400
   Full Text »    PDF »
Science Signaling Podcast: 8 May 2012.
M. T. Nelson and A. M. VanHook (2012)
Science Signaling 5, pc10
   Abstract »    Full Text »
Superresolution Subspace Signaling.
W. J. Lederer, B. M. Hagen, and G. Zhao (2012)
Science 336, 546-547
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882