Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange
Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange
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DOI：
10.1073/pnas.0606728103
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发表时间：
2006-12-12
影响因子：
11.1
通讯作者：
Gudermann, Thomas
中科院分区：
文献类型：
--
作者：
Weissmann, Norbert;Dietrich, Alexander;Gudermann, Thomas
局部肺泡缺氧导致肺部局部血管收缩，将血流从缺氧区域转移到含氧量正常区域，从而维持气体交换。这种机制被称为缺氧性肺血管收缩（HPV）。 HPV 干扰可导致危及生命的低氧血症，而慢性低氧则会引发肺血管重塑和肺动脉高压。这一极其重要的机制的信号级联仍未得到解决。使用瞬时受体电位通道 6 (TRPC6) 缺陷小鼠，我们发现该通道是急性 HPV 的关键调节因子，因为 TRPC6(-/-) 小鼠中不存在这种调节机制，而对血栓素模拟物 U46619 的肺血管收缩反应则没有变化。因此，局部通气不足的诱导导致 TRPC6(-/-) 小鼠严重动脉低氧血症，但 WT 小鼠则不然。 TRPC6(-/-) 小鼠毛细血管前肺动脉 (PASMC) 平滑肌细胞缺乏缺氧诱导的阳离子流入和电流，反映了这种效应。在WT和TRPC6(-/-) PASMC中，缺氧导致二酰甘油(DAG)积累。 DAG 似乎通过 TRPC6 发挥作用，因为 DAG 激酶抑制仅在 WT 中引起阳离子流入，而在 TRPC6(-/-) PASMC 中则不然。值得注意的是，慢性缺氧引起的肺动脉高压与 TRPC6 活性无关。我们得出结论，TRPC6 在急性缺氧性肺血管收缩中发挥着独特且不可或缺的作用。因此，TRPC6 功能的调控可能为控制肺血流动力学和气体交换提供一种治疗策略。
Regional alveolar hypoxia causes local vasoconstriction in the lung, shifting blood flow from hypoxic to normoxic areas, thereby maintaining gas exchange. This mechanism is known as hypoxic pulmonary vasoconstriction (HPV). Disturbances in HPV can cause life-threatening hypoxemia whereas chronic hypoxia triggers lung vascular remodeling and pulmonary hypertension. The signaling cascade of this vitally important mechanism is still unresolved. Using transient receptor potential channel 6 (TRPC6)-deficient mice, we show that this channel is a key regulator of acute HPV as this regulatory mechanism was absent in TRPC6(-/-) mice whereas the pulmonary vasoconstrictor response to the thromboxane mimetic U46619 was unchanged. Accordingly, induction of regional hypoventilation resulted in severe arterial hypoxemia in TRPC6(-/-) but not in WT mice. This effect was mirrored by a lack of hypoxia-induced cation influx and currents in smooth-muscle cells from precapillary pulmonary arteries (PASMC) of TRPC6(-/-) mice. In both WT and TRPC6(-/-) PASMC hypoxia caused diacylglycerol (DAG) accumulation. DAG seems to exert its action via TRPC6, as DAG kinase inhibition provoked a cation influx only in WT but not in TRPC6(-/-) PASMC. Notably, chronic hypoxia-induced pulmonary hypertension was independent of TRPC6 activity. We conclude that TRPC6 plays a unique and indispensable role in acute hypoxic pulmonary vasoconstriction. Manipulation of TRPC6 function may thus offer a therapeutic strategy for the control of pulmonary hemodynamics and gas exchange.