%0 Journal Article
%T The LKB1¨CAMPK-¦Á1 signaling pathway triggers hypoxic pulmonary vasoconstriction downstream of mitochondria
%J -
%D 2018
%R 10.1126/scisignal.aau0296
%X 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¨CAMPK-¦Á1 signaling pathway is critical to HPV. Spectral Doppler ultrasound revealed that deletion of the AMPK-¦Á1 catalytic subunit blocked HPV in mice during mild (8% O2) and severe (5% O2) hypoxia, whereas AMPK-¦Á2 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-¦Á1 or AMPK-¦Á2 deletion did not affect mitochondrial membrane potential during normoxia or hypoxia. However, deletion of AMPK-¦Á1, but not of AMPK-¦Á2, blocked hypoxia from inhibiting KV1.5, the classical ¡°oxygen-sensing¡± K+ channel in pulmonary arterial myocytes. We conclude that LKB1¨CAMPK-¦Á1 signaling pathways downstream of mitochondria are critical for the induction of HPV, in a manner also supported by AMPK-¦Á2 during severe hypoxia
%U http://stke.sciencemag.org/content/11/550/eaau0296