Crucial role of phospholipase C gamma 2 in hypoxic pulmonary vasoconstriction

Abstract

Hypoxic pulmonary vasoconstriction (HPV) may ensure the physiological regional alveolar ventilation‐pulmonary perfusion matching, but can also serve as a key pathological mechanism leading to pulmonary hypertension and associated right ventricular failure. An increase in [Ca2+]i in pulmonary artery smooth muscle cells (PASMCs) is vital for HPV. However, the underlying molecular mechanisms remain incompletely understood. We have found that acute hypoxia significantly increases the activity of total phospholipase C (PLC) in isolated, endothelium‐denuded mouse resistance pulmonary arteries. The activity of PLCγ2 is largely augmented as well following hypoxic exposure. The PLC inhibitor U73122 (1 μM) greatly diminishes the hypoxia‐induced increase in [Ca2+]i in PASMCs, whereas U73433 (1 μM), an inactive analog of U73122, has no effect. 2‐aminoethoxydiphenyl borate (2‐APB) and xestospongin C to block inositol trisphosphate receptors (IP3Rs) also inhibit the hypoxic Ca2+ response. Excitingly, shRNA‐mediated PLCγ2 gene silencing diminishes the hypoxia‐induced increase in [Ca2+]i. Using myxothiazol to inhibit mitochondrial ROS production blocks the hypoxic activation of PLCγ2. In conclusion, hypoxia can specifically activate PLCγ2 and then IP3Rs to increase [Ca2+]i in PASMCs by enhancing mitochondrial ROS production, which may play an important role in HPV and hypoxic pulmonary hypertension. This study was supported by AHA EIA 0340160N and NIH R01 HL64043, HL064043‐S1, and HL075190.