EP3 Blockade Adds to the Effect of TP Deficiency in Alleviating Endothelial Dysfunction in Atherosclerotic Mouse Aortas
EP3 Blockade Adds to the Effect of TP Deficiency in Alleviating Endothelial Dysfunction in Atherosclerotic Mouse Aortas
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EP3 阻断增强了 TP 缺乏对缓解动脉粥样硬化小鼠主动脉内皮功能障碍的作用
DOI：
10.3389/fphys.2019.01247
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发表时间：
2019-09-26
影响因子：
4
通讯作者：
Zhou, Yingbi
中科院分区：
文献类型：
--
作者：
Hu, Chuangjia;Liu, Bin;Zhou, Yingbi
在动脉粥样硬化条件下导致缺血事件的内皮功能障碍可以通过拮抗血栓素-前列腺素类受体（TP）来减弱，所述血栓素-前列腺素类受体（TP）介导前列腺素类（包括前列环素（PGI2））的血管收缩作用。本研究旨在确定在动脉粥样硬化条件下，拮抗E前列腺素受体-3（EP3;也可被PGI2激活）是否会增加TP缺乏（TP-/-）的上述作用，如果是，则确定其潜在机制。在ApoE-/-小鼠和ApoE-/-和TP-/-小鼠中诱导动脉粥样硬化。在这里，我们表明，在苯乙哌啶预收缩的腹主动脉环与动脉粥样硬化病变的ApoE-/-/TP-/-小鼠，虽然增加的力量，内皮毒蕈碱激动剂乙酰胆碱诱发的抑制ApoE-/-对应物中同时激活的舒张的血管收缩（大于非动脉粥样硬化对照）在很大程度上被消除，激动剂诱发的舒张仍然小于非动脉粥样硬化TP-/-小鼠。EP3拮抗不仅增加上述舒张作用，而且逆转了乙酰胆碱诱发的NO还原酶抑制的动脉粥样硬化ApoE-/-/TP-/-环的收缩反应，使其变为对前列腺素I受体拮抗敏感的舒张反应。在ApoE-/-动脉粥样硬化血管的内皮NO合酶的表达减少，但生产的PGI2（引起收缩通过TP和EP3）引起的乙酰胆碱是不变的相比，非动脉粥样硬化的条件。这些结果表明，EP3阻断增加了TP-/-在揭示天然产生的PGI2的扩张作用以减轻动脉粥样硬化状况中的内皮功能障碍方面的作用。
Endothelial dysfunction, which leads to ischemic events under atherosclerotic conditions, can be attenuated by antagonizing the thromboxane-prostanoid receptor (TP) that mediates the vasoconstrictor effect of prostanoids including prostacyclin (PGI2). This study aimed to determine whether antagonizing the E prostanoid receptor-3 (EP3; which can also be activated by PGI2) adds to the above effect of TP deficiency (TP–/–) under atherosclerotic conditions and if so, the underlying mechanism(s). Atherosclerosis was induced in ApoE–/– mice and those with ApoE–/– and TP–/–. Here, we show that in phenylephrine pre-contracted abdominal aortic rings with atherosclerotic lesions of ApoE–/–/TP–/– mice, although an increase of force (which was larger than that of non-atherosclerotic controls) evoked by the endothelial muscarinic agonist acetylcholine to blunt the concurrently activated relaxation in ApoE–/– counterparts was largely removed, the relaxation evoked by the agonist was still smaller than that of non-atherosclerotic TP–/– mice. EP3 antagonism not only increased the above relaxation, but also reversed the contractile response evoked by acetylcholine in NO synthase-inhibited atherosclerotic ApoE–/–/TP–/– rings into a relaxation sensitive to I prostanoid receptor antagonism. In ApoE–/– atherosclerotic vessels the expression of endothelial NO synthase was decreased, yet the production of PGI2 (which evokes contraction via both TP and EP3) evoked by acetylcholine was unaltered compared to non-atherosclerotic conditions. These results demonstrate that EP3 blockade adds to the effect of TP–/– in uncovering the dilator action of natively produced PGI2 to alleviate endothelial dysfunction in atherosclerotic conditions.