Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.
Division of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21224, USA.
Anal Cell Pathol (Amst). 2020 Jan 22;2020:8927381. doi: 10.1155/2020/8927381. eCollection 2020.
Transient receptor potential vanilloid 4 (TRPV4) is a multi-functional non-selective channel expressed in pulmonary vasculatures. TRPV4 contributes to serotonin- (5-HT-) induced pulmonary vasoconstriction and is responsible in part for the enhanced 5-HT response in pulmonary arteries (PAs) of chronic hypoxia mice. Epoxyeicosatrienoic acid (EET) is an endogenous agonist of TRPV4 and is known to regulate vasoreactivity. The levels of EETs, the expression of cytochrome P450 (CYP) epoxygenase for EET production, and epoxide hydrolase for EET degradation are altered by chronic hypoxia. Here, we examined the role of EET-dependent TRPV4 activation in the 5-HT-mediated PA contraction. In PAs of normoxic mice, inhibition of TRPV4 with a specific inhibitor HC-067047 caused a decrease in the sensitivity of 5-HT-induced PA contraction without affecting the maximal contractile response. Application of the cytochrome P450 epoxygenase inhibitor MS-PPOH had no effect on the vasoreactivity to 5-HT. In contrast, inhibition of CYP epoxygenase or TRPV4 both attenuated the 5-HT-elicited maximal contraction to a comparable level in PAs of chronic hypoxic mice. Moreover, the inhibitory effect of MS-PPOH on the 5-HT-induced contraction was obliterated in PAs of chronic hypoxic mice. These results suggest that TRPV4 contributes to the enhanced 5-HT-induced vasoconstriction in chronic hypoxic PAs, in part via the CYP-EET-TRPV4 pathway. Our results further support the notion that manipulation of TRPV4 function may offer a novel therapeutic strategy for the treatment of hypoxia-related pulmonary hypertension.
瞬时受体电位香草酸亚型 4（TRPV4）是一种多功能非选择性通道，在肺血管中表达。TRPV4 有助于 5-羟色胺（5-HT）诱导的肺血管收缩，部分负责慢性低氧小鼠肺动脉中增强的 5-HT 反应。环氧二十碳三烯酸（EET）是 TRPV4 的内源性激动剂，已知可调节血管反应性。EETs 的水平、EET 产生的细胞色素 P450（CYP）环氧合酶的表达以及 EET 降解的环氧化物水解酶在慢性低氧下发生改变。在这里，我们研究了 EET 依赖性 TRPV4 激活在 5-HT 介导的 PA 收缩中的作用。在正常氧小鼠的肺动脉中，用特异性抑制剂 HC-067047 抑制 TRPV4 会降低 5-HT 诱导的 PA 收缩的敏感性，而不影响最大收缩反应。应用细胞色素 P450 环氧合酶抑制剂 MS-PPOH 对 5-HT 的血管反应性没有影响。相比之下，抑制 CYP 环氧合酶或 TRPV4 均使慢性低氧小鼠的肺动脉中 5-HT 引起的最大收缩减弱到相当水平。此外，MS-PPOH 对 5-HT 诱导的收缩的抑制作用在慢性低氧小鼠的肺动脉中被消除。这些结果表明，TRPV4 部分通过 CYP-EET-TRPV4 途径参与增强慢性低氧肺动脉中 5-HT 诱导的血管收缩。我们的结果进一步支持了这样一种观点，即操纵 TRPV4 功能可能为治疗与缺氧相关的肺动脉高压提供一种新的治疗策略。
