Notch activation of Ca<sup>2+</sup> signaling in the development of hypoxic pulmonary vasoconstriction and pulmonary hypertension

Kimberly A. Smith, Guillaume Voiriot, Haiyang Tang, Dustin R. Fraidenburg, Shanshan Song, Hisao Yamamura, Aya Yamamura, Qiang Guo, Jun Wan, Nicole M. Pohl, Mohammad Tauseef, Rolf Bodmer, Karen Ocorr, Patricia A. Thistlethwaite, Gabriel G. Haddad, Frank L. Powell, Ayako Makino, Dolly Mehta, Jason Yuan

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

Hypoxic pulmonary vasoconstriction (HPV) is an important physiological response that optimizes the ventilation/perfusion ratio. Chronic hypoxia causes vascular remodeling, which is central to the pathogenesis of hypoxia-induced pulmonary hypertension (HPH). We have previously shown that Notch3 is up-regulated in HPH and that activation of Notch signaling enhances store-operated Ca<sup>2+</sup> entry (SOCE), an important mechanism that contributes to pulmonary arterial smooth muscle cell (PASMC) proliferation and contraction. Here, we investigate the role of Notch signaling in HPV and hypoxia-induced enhancement of SOCE. We examined SOCE in human PASMCs exposed to hypoxia and pulmonary arterial pressure in mice using the isolated perfused/ventilated lung method. Wildtype and canonical transient receptor potential (TRPC) 6<sup>-/-</sup> mice were exposed to chronic hypoxia to induce HPH. Inhibition of Notch signaling with a γ-secretase inhibitor attenuates hypoxia-enhanced SOCE in PASMCs and hypoxia-induced increase in pulmonary arterial pressure. Our results demonstrate that hypoxia activates Notch signaling and up-regulates TRPC6 channels. Additionally, treatment with a Notch ligand can mimic hypoxic responses. Finally, inhibition of TRPC6, either pharmacologically or genetically, attenuates HPV, hypoxia-enhanced SOCE, and the development of HPH. These results demonstrate that hypoxia-induced activation of Notch signaling mediates HPV and the development of HPH via functional activation and up-regulation of TRPC6 channels. Understanding the molecular mechanisms that regulate cytosolic free Ca<sup>2+</sup> concentration and PASMC proliferation is critical to elucidation of the pathogenesis of HPH. Targeting Notch regulation of TRPC6 will be beneficial in the development of novel therapies for pulmonary hypertension associated with hypoxia.

Original languageEnglish (US)
Pages (from-to)355-367
Number of pages13
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume53
Issue number3
DOIs
StatePublished - Sep 1 2015

Keywords

  • Hypoxia
  • Notch
  • Pulmonary artery
  • Store-operated Ca<sup>2+</sup> entry
  • TRPC6

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

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  • Cite this

    Smith, K. A., Voiriot, G., Tang, H., Fraidenburg, D. R., Song, S., Yamamura, H., Yamamura, A., Guo, Q., Wan, J., Pohl, N. M., Tauseef, M., Bodmer, R., Ocorr, K., Thistlethwaite, P. A., Haddad, G. G., Powell, F. L., Makino, A., Mehta, D., & Yuan, J. (2015). Notch activation of Ca<sup>2+</sup> signaling in the development of hypoxic pulmonary vasoconstriction and pulmonary hypertension. American Journal of Respiratory Cell and Molecular Biology, 53(3), 355-367. https://doi.org/10.1165/rcmb.2014-0235OC