Goldenberg Neil M, Wang Liming, Ranke Hannes, Liedtke Wolfgang, Tabuchi Arata, Kuebler Wolfgang M
From the Department of Anesthesia, University of Toronto, Toronto, Ontario, Canada (N.M.G.); the Keenan Research Centre at the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada (L.W., A.T., W.M.K.); Institute of Physiology, Charité-University Berlin, Berlin, Germany (H.R., W.M.K.); Duke Institute for Brain Sciences, Duke University, Durham, North Carolina (W.L.); German Heart Institute Berlin, Berlin, Germany (W.M.K.); and Departments of Physiology and Surgery, University of Toronto, Toronto, Ontario, Canada (W.M.K.).
Anesthesiology. 2015 Jun;122(6):1338-48. doi: 10.1097/ALN.0000000000000647.
Hypoxic pulmonary vasoconstriction (HPV) is critically important in regionally heterogeneous lung diseases by directing blood toward better-oxygenated lung units, yet the molecular mechanism of HPV remains unknown. Transient receptor potential (TRP) channels are a large cation channel family that has been implicated in HPV, specifically in the pulmonary artery smooth muscle cell (PASMC) Ca and contractile response to hypoxia. In this study, the authors probed the role of the TRP family member, TRPV4, in HPV.
HPV was assessed by using isolated perfused mouse lungs or by intravital microscopy to directly visualize pulmonary arterioles in mice. In vitro experiments were performed in primary human PASMC.
The hypoxia-induced pulmonary artery pressure increase seen in wild-type mice (5.6 ± 0.6 mmHg; mean ± SEM) was attenuated both by inhibition of TRPV4 (2.8 ± 0.5 mmHg), or in lungs from TRPV4-deficient mice (Trpv4) (3.4 ± 0.5 mmHg; n = 7 each). Functionally, Trpv4 mice displayed an exaggerated hypoxemia after regional airway occlusion (paO2 71% of baseline ± 2 vs. 85 ± 2%; n = 5). Direct visualization of pulmonary arterioles by intravital microscopy revealed a 66% reduction in HPV in Trpv4 mice. In human PASMC, inhibition of TRPV4 blocked the hypoxia-induced Ca influx and myosin light chain phosphorylation. TRPV4 may form a heteromeric channel with TRPC6 as the two channels coimmunoprecipitate from PASMC and as there is no additive effect of TRPC and TRPV4 inhibition on Ca influx in response to the agonist, 11,12-epoxyeicosatrienoic acid.
TRPV4 plays a critical role in HPV, potentially via cooperation with TRPC6.
缺氧性肺血管收缩（HPV）在区域异质性肺部疾病中至关重要，它可将血液导向氧合较好的肺单位，但HPV的分子机制仍不清楚。瞬时受体电位（TRP）通道是一个大的阳离子通道家族，与HPV有关，特别是在肺动脉平滑肌细胞（PASMC）对缺氧的钙反应和收缩反应中。在本研究中，作者探讨了TRP家族成员TRPV4在HPV中的作用。
通过使用离体灌注小鼠肺或活体显微镜直接观察小鼠肺小动脉来评估HPV。在原代人PASMC中进行体外实验。
野生型小鼠中观察到的缺氧诱导的肺动脉压力升高（5.6±0.6 mmHg；平均值±标准误）在TRPV4受到抑制时（2.8±0.5 mmHg）或在TRPV4基因敲除小鼠（Trpv4）的肺中（3.4±0.5 mmHg；每组n = 7）均减弱。在功能上，Trpv4小鼠在局部气道阻塞后出现了更严重的低氧血症（动脉血氧分压为基线的71%±2，而野生型为85±2%；n = 5）。通过活体显微镜直接观察肺小动脉发现，Trpv4小鼠的HPV降低了66%。在人PASMC中，抑制TRPV4可阻断缺氧诱导的钙内流和肌球蛋白轻链磷酸化。TRPV4可能与TRPC6形成异源通道，因为这两个通道可从PASMC中共免疫沉淀，并且TRPC和TRPV4抑制对激动剂11,12-环氧二十碳三烯酸诱导的钙内流没有叠加效应。
TRPV4在HPV中起关键作用，可能是通过与TRPC6协同作用。
