3 years ago

Important role of endothelium-dependent hyperpolarization in pulmonary microcirculation in male mice -Implications for hypoxia-induced pulmonary hypertension.

Shuhei Tanaka, Shoko Kajitani, Takashi Shiroto, Hiroaki Shimokawa, Akiyo Ito, Yosuke Ikumi, Shigeo Godo, Hiroki Saito, Saori Sato
Endothelium-dependent hyperpolarization (EDH) plays important roles in systemic circulation, whereas its role in pulmonary circulation remains largely unknown. Furthermore, the underlying mechanisms of pulmonary hypertension (PH) also remain to be elucidated. We thus aimed to elucidate the role of EDH in pulmonary circulation in general and in PH in particular. In isolated perfused lung using male wild-type mice, endothelium-dependent relaxations to bradykinin (BK) were significantly reduced in the presence of Nω-nitro-L-arginine (L-NNA) by ~50% as compared with those in the presence of indomethacin, and the combination of apamin plus charybdotoxin abolished the residual relaxations, showing the comparable contributions of nitric oxide (NO) and EDH in pulmonary microcirculation under physiological conditions. Catalase markedly inhibited EDH-mediated relaxations, indicating the predominant contribution of endothelium-derived hydrogen peroxide. BK-mediated relaxations were significantly reduced at day 1 of hypoxia, while thereafter remained unchanged until day 28. EDH-mediated relaxations were diminished at day 2 of hypoxia, indicating a transition from EDH to NO in BK-mediated relaxations prior to the development of hypoxia-induced PH. Mechanistically, chronic hypoxia enhanced eNOS expression and activity associated with downregulation of caveolin-1. Nitrotyrosine levels were significantly higher in vascular smooth muscle of pulmonary microvessels under chronic hypoxia than under normoxia. Similar transition of the mediators in BK-mediated relaxations was also noted in Sugen hypoxia mouse model. These results indicate that EDH plays important roles in pulmonary microcirculation in addition to NO under normoxic conditions and that impaired EDH-mediated relaxations and subsequent nitrosative stress may be potential triggers of the onset of PH.

Publisher URL: http://doi.org/10.1152/ajpheart.00487.2017

DOI: 10.1152/ajpheart.00487.2017

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