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 trpv4^-/- 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.

中文翻译：

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细胞色素P450环氧酶依赖性激活的TRPV4通道参与了慢性低氧性肺动脉高压中由5-羟色胺诱导的肺血管收缩。

瞬时受体电位香草酸4（TRPV4）是在肺血管系统中表达的多功能非选择性通道。TRPV4有助于血清素（5-HT-）诱导的肺血管收缩，部分负责慢性低氧小鼠的肺动脉（PA）中的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。慢性缺氧会改变EET的水平，产生EET的细胞色素P450（CYP）环氧酶的表达以及降解EET的环氧水解酶。在这里，我们检查了EET依赖性TRPV4激活在5-HT介导的PA收缩中的作用。在常氧小鼠的PA中，用特异性抑制剂HC-067047抑制TRPV4会导致5-HT诱导的PA收缩敏感性降低，而不会影响最大的收缩反应。细胞色素P450环氧酶抑制剂MS-PPOH的使用对5-HT的血管反应性没有影响。相反，在慢性低氧小鼠的PA中，CYP环氧酶或TRPV4的抑制都将5-HT引起的最大收缩减至可比较的水平。此外，在慢性低氧的PA中，MS-PPOH对5-HT诱导的收缩的抑制作用被消除。trpv4 ^-/-小鼠。这些结果表明，TRPV4部分通过CYP-EET-TRPV4途径促进了慢性低氧PAs中5-HT诱导的血管收缩。我们的结果进一步支持以下观点：TRPV4功能的操纵可能为缺氧相关性肺动脉高压的治疗提供新的治疗策略。