09 Oct 18. Featured Paper

Link to paper on Science Signaling.

Authors

Javier Moral-Sanz, Sophronia A. Lewis, Sandy MacMillan, Fiona A. Ross, Adrian Thomson, Benoit Viollet, Marc Foretz, Carmel Moran, D. Grahame Hardie, and A. Mark Evans

Abstract

Hypoxic pulmonary vasoconstriction (HPV), which aids ventilation-perfusion matching in the lungs, is triggered by mechanisms intrinsic to pulmonary arterial smooth muscles. The unique sensitivity of these muscles to hypoxia is conferred by mitochondrial cytochrome c oxidase subunit 4 isoform 2, the inhibition of which has been proposed to trigger HPV through increased generation of mitochondrial reactive oxygen species. Contrary to this model, we have shown that the LKB1–AMPK-α1 signaling pathway is critical to HPV. Spectral Doppler ultrasound revealed that deletion of the AMPK-α1 catalytic subunit blocked HPV in mice during mild (8% O₂) and severe (5% O₂) hypoxia, whereas AMPK-α2 deletion attenuated HPV only during severe hypoxia. By contrast, neither of these genetic manipulations affected serotonin-induced reductions in pulmonary vascular flow. HPV was also attenuated by reduced expression of LKB1, a kinase that activates AMPK during energy stress, but not after deletion of CaMKK2, a kinase that activates AMPK in response to increases in cytoplasmic Ca²⁺. Fluorescence imaging of acutely isolated pulmonary arterial myocytes revealed that AMPK-α1 or AMPK-α2 deletion did not affect mitochondrial membrane potential during normoxia or hypoxia. However, deletion of AMPK-α1, but not of AMPK-α2, blocked hypoxia from inhibiting K_V1.5, the classical “oxygen-sensing” K⁺ channel in pulmonary arterial myocytes. We conclude that LKB1–AMPK-α1 signaling pathways downstream of mitochondria are critical for the induction of HPV, in a manner also supported by AMPK-α2 during severe hypoxia.

Keywords

• Hypoxic pulmonary vasoconstriction (HPV)
• Ultrasound
• AMPK-alpha1
• AMPK-alpha2
• LBK1