Caveolar peroxynitrite formation impairs endothelial TRPV4 channels and elevates pulmonary arterial pressure in pulmonary hypertension

Zdravka Daneva, Corina Marziano, Matteo Ottolini, Yen Lin Chen, Thomas M. Baker, Maniselvan Kuppusamy, Aimee Zhang, Huy Q. Ta, Claire E. Reagan, Andrew D. Mihalek, Ramesh B. Kasetti, Yuanjun Shen, Brant E. Isakson, Richard D. Minshall, Gulab S. Zode, Elena A. Goncharova, Victor E. Laubach, Swapnil K. Sonkusare

Research output: Contribution to journalArticlepeer-review

Abstract

Recent studies have focused on the contribution of capillary endothelial TRPV4 channels to pulmonary pathologies, including lung edema and lung injury. However, in pulmonary hypertension (PH), small pulmonary arteries are the focus of the pathology, and endothelial TRPV4 channels in this crucial anatomy remain unexplored in PH. Here, we provide evidence that TRPV4 channels in endothelial cell caveolae maintain a low pulmonary arterial pressure under normal conditions. Moreover, the activity of caveolar TRPV4 channels is impaired in pulmonary arteries from mouse models of PH and PH patients. In PH, up-regulation of iNOS and NOX1 enzymes at endothelial cell caveolae results in the formation of the oxidant molecule peroxynitrite. Peroxynitrite, in turn, targets the structural protein caveolin-1 to reduce the activity of TRPV4 channels. These results suggest that endothelial caveolin-1–TRPV4 channel signaling lowers pulmonary arterial pressure, and impairment of endothelial caveolin-1–TRPV4 channel signaling contributes to elevated pulmonary arterial pressure in PH. Thus, inhibiting NOX1 or iNOS activity, or lowering endothelial peroxynitrite levels, may represent strategies for restoring vasodilation and pulmonary arterial pressure in PH.

Original languageEnglish
Article numbere2023130118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number17
DOIs
StatePublished - 27 Apr 2021

Keywords

  • Caveolin
  • Endothelium
  • Peroxynitrite
  • Pulmonary hypertension
  • TRP channel

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