Functional coupling of TRPV4, IK, and SK channels contributes to Ca2+-dependent endothelial injury in rodent lung

Abstract

Our previous work has shown that the increased lung endothelial permeability response to 14,15-epoxyeicosatrienoic acid (14,15-EET) in rat lung requires Ca2+ entry via vanilloid type-4 transient receptor potential (TRPV4) channels. Recent studies suggest that activation of TRPV4 channels in systemic vascular endothelium prolongs agonist-induced hyperpolarization and amplifies Ca2+entry by activating Ca2+-activated K+ (KCa) channels, resulting in vessel relaxation. Activation of endothelial KCa channels thus has potential to increase the electrochemical driving force for Ca2+influx via TRPV4 channels and to amplify permeability responses to TRPV4 activation in lung. To examine this hypothesis, we used Western blot analysis, electrophysiological recordings, and isolated-lung permeability measurements to document expression of TRPV4 and KCa channels and the potential for functional coupling. The results show that rat pulmonary microvascular endothelial cells express TRPV4 and 3 KCa channels of different conductances: large (BK), intermediate (IK), and small (SK3). However, TRPV4 channel activity modulates the IK and SK3, but not the BK, channel current density. Furthermore, the TRPV4-mediated permeability response to 14,15-EET in mouse lung is significantly attenuated by pharmacologic blockade of IK and SK3, but not BK, channels. Collectively, this functional coupling suggests that endothelial TRPV4 channels in rodent lung likely form signaling microdomains with IK and SK3 channels and that the integrated response dictates the extent of lung endothelial injury caused by 14,15-EET.

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Topics

Lung Repair and Regeneration
Preclinical and Molecular Science
Pulmonary Endothelium

Authors

Mike T. Lin, Ming-Yuan Jian, Mark S. Taylor, Donna L. Cioffi, Fui C. Yap, Wolfgang Liedtke, Mary I. Townsley

Published in:

Pulmonary Circulation Vol 5: No 2 cover image

June 2015

Pulmonary Circulation Vol 5: No 2

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