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Upregulation of osmo-mechanosensitive TRPV4 channel facilitates chronic hypoxia-induced myogenic tone and pulmonary hypertension.

Publication ,  Journal Article
Yang, X-R; Lin, AHY; Hughes, JM; Flavahan, NA; Cao, Y-N; Liedtke, W; Sham, JSK
Published in: Am J Physiol Lung Cell Mol Physiol
March 15, 2012

Chronic hypoxia causes pulmonary hypertension with vascular remodeling, increase in vascular tone, and altered reactivity to agonists. These changes involve alterations in multiple Ca(2+) pathways in pulmonary arterial smooth muscle cells (PASMCs). We have previously shown that vanilloid (TRPV)- and melastatin-related transient receptor potential (TRPM) channels are expressed in pulmonary arteries (PAs). Here we found that TRPV4 was the only member of the TRPV and TRPM subfamilies upregulated in PAs of chronic hypoxic rats. The increase in TRPV4 expression occurred within 1 day of hypoxia exposure, indicative of an early hypoxic response. TRPV4 in PASMCs were found to be mechanosensitive. Osmo-mechanical stress imposed by hypotonic solution activated Ca(2+) transients; they were inhibited by TRPV4 specific short interfering RNA, the TRPV blocker ruthenium red, and the cytochrome P450 epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide. Consistent with TRPV4 upregulation, the Ca(2+) response induced by the TRPV4 agonist 4α-phorbol 12,13-didecanoate and hypotonicity was potentiated in hypoxic PASMCs. Moreover, a significant myogenic tone, sensitive to ruthenium red, was observed in pressurized endothelium denuded small PAs of hypoxic but not normoxic rats. The elevated basal intracellular Ca(2+) concentration in hypoxic PASMCs was also reduced by ruthenium red. In extension of these results, the development of pulmonary hypertension, right heart hypertrophy, and vascular remodeling was significantly delayed and suppressed in hypoxic trpv4(-/-) mice. These results suggest the novel concept that TRPV4 serves as a signal pathway crucial for the development of hypoxia-induced pulmonary hypertension. Its upregulation may provide a pathogenic feed-forward mechanism that promotes pulmonary hypertension via facilitated Ca(2+) influx, subsequently enhanced myogenic tone and vascular remodeling.

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Published In

Am J Physiol Lung Cell Mol Physiol

DOI

EISSN

1522-1504

Publication Date

March 15, 2012

Volume

302

Issue

6

Start / End Page

L555 / L568

Location

United States

Related Subject Headings

  • Up-Regulation
  • TRPV Cation Channels
  • Respiratory System
  • Rats, Wistar
  • Rats
  • Pulmonary Artery
  • Myocytes, Smooth Muscle
  • Muscle, Smooth, Vascular
  • Microvessels
  • Mice, Knockout
 

Citation

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Chicago
ICMJE
MLA
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Yang, X.-R., Lin, A. H. Y., Hughes, J. M., Flavahan, N. A., Cao, Y.-N., Liedtke, W., & Sham, J. S. K. (2012). Upregulation of osmo-mechanosensitive TRPV4 channel facilitates chronic hypoxia-induced myogenic tone and pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol, 302(6), L555–L568. https://doi.org/10.1152/ajplung.00005.2011
Yang, Xiao-Ru, Amanda H. Y. Lin, Jennifer M. Hughes, Nicholas A. Flavahan, Yuan-Ning Cao, Wolfgang Liedtke, and James S. K. Sham. “Upregulation of osmo-mechanosensitive TRPV4 channel facilitates chronic hypoxia-induced myogenic tone and pulmonary hypertension.Am J Physiol Lung Cell Mol Physiol 302, no. 6 (March 15, 2012): L555–68. https://doi.org/10.1152/ajplung.00005.2011.
Yang X-R, Lin AHY, Hughes JM, Flavahan NA, Cao Y-N, Liedtke W, et al. Upregulation of osmo-mechanosensitive TRPV4 channel facilitates chronic hypoxia-induced myogenic tone and pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2012 Mar 15;302(6):L555–68.
Yang, Xiao-Ru, et al. “Upregulation of osmo-mechanosensitive TRPV4 channel facilitates chronic hypoxia-induced myogenic tone and pulmonary hypertension.Am J Physiol Lung Cell Mol Physiol, vol. 302, no. 6, Mar. 2012, pp. L555–68. Pubmed, doi:10.1152/ajplung.00005.2011.
Yang X-R, Lin AHY, Hughes JM, Flavahan NA, Cao Y-N, Liedtke W, Sham JSK. Upregulation of osmo-mechanosensitive TRPV4 channel facilitates chronic hypoxia-induced myogenic tone and pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2012 Mar 15;302(6):L555–L568.

Published In

Am J Physiol Lung Cell Mol Physiol

DOI

EISSN

1522-1504

Publication Date

March 15, 2012

Volume

302

Issue

6

Start / End Page

L555 / L568

Location

United States

Related Subject Headings

  • Up-Regulation
  • TRPV Cation Channels
  • Respiratory System
  • Rats, Wistar
  • Rats
  • Pulmonary Artery
  • Myocytes, Smooth Muscle
  • Muscle, Smooth, Vascular
  • Microvessels
  • Mice, Knockout