Prostaglandin F2α evokes vasoconstrictor and vasodepressor activities that are both independent of the F prostanoid receptor
Prostaglandin F2α evokes vasoconstrictor and vasodepressor activities that are both independent of the F prostanoid receptor
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DOI：
10.1096/fj.202101908r
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发表时间：
2022-05
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通讯作者：
Ruhui Zeng;Bin Liu;Tingting Guo;Jinwei Guo;Gang Yu;Yineng Xu;R. Lin;Xiangzhai Tan;Kaiqi Xie;Yingbi Zhou
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作者：
Ruhui Zeng;Bin Liu;Tingting Guo;Jinwei Guo;Gang Yu;Yineng Xu;R. Lin;Xiangzhai Tan;Kaiqi Xie;Yingbi Zhou
F前列腺素受体（FP）介导了PGF2α对子宫收缩乏力（可导致产后出血和产妇发病）的治疗作用，但它也可能介导小动脉或阻力动脉的血管收缩效应，从而升高血压，这限制了该药物在心血管疾病患者中的临床应用。本研究旨在利用基因改造小鼠验证上述假设。对对照野生型（WT）小鼠、FP缺陷型小鼠（FP−/−）、血栓素（Tx） - 前列腺素受体（TxA2的原始受体；TP−/−）缺陷型小鼠，以及/或者额外存在E前列腺素受体 - 3（PGE2的血管收缩受体之一；EP3−/−）缺陷的小鼠进行了离体和在体实验。在此，我们发现PGF2α确实能在野生型小鼠上述组织中引发血管收缩反应，但该反应在FP−/−小鼠中并无改变。有趣的是，在TP−/−/EP3−/−小鼠中，这种收缩反应转变为舒张反应。在体内条件下，PGF2α的升压效应也观察到类似的结果模式。然而，单独的TP−/−（可在很大程度上消除收缩反应）并不会使PGF2α引发舒张反应。此外，去除TP和EP3介导的作用后，PGF2α的离体血管舒张效应或在体降压反应在FP−/−小鼠中均未改变。因此，PGF2α在小动脉或阻力动脉中的离体血管收缩作用以及全身升压效应，都反映出非FP受体TP和EP3产生的血管收缩活性超过了同时激活的舒张效应，且这一过程同样与FP无关。
The F prostanoid receptor (FP), which accounts for the therapeutic effect of PGF2α in uterine atony that leads to postpartum hemorrhage and maternal morbidity, could possibly mediate vasoconstrictor effect in small or resistance arteries to elevate blood pressure that limits the clinical use of the agent in patients with cardiovascular disorders. This study aimed to test the above hypothesis with genetically altered mice. Ex vivo and in vivo experiments were performed on control wild‐type (WT) mice and mice with deficiencies in FP (FP−/−) or thromboxane (Tx)‐prostanoid receptor (the original receptor of TxA2; TP−/−), and/or those with an additional deficiency in E prostanoid receptor‐3 (one of the vasoconstrictor receptors of PGE2; EP3−/−). Here, we show that PGF2α indeed evoked vasoconstrictor responses in the above‐mentioned tissues of WT mice, which were however unaltered by FP−/−. Interestingly, such contractile responses were reversed into dilations by TP−/−/EP3−/−. A similar pattern of results was observed with the pressor effect of PGF2α under in vivo conditions. However, TP−/− alone (which could largely remove the contractile responses) did not result in relaxation to PGF2α. Also, either the ex vivo vasodilator effect or the in vivo depressor response of PGF2α obtained after the removal of TP and EP3‐mediated actions was unaltered by FP−/−. Therefore, both the ex vivo vasoconstrictor action in small or resistance arteries and the systemic pressor effect of PGF2α can reflect vasoconstrictor activities derived from the non‐FP receptors TP and EP3 outweighing a concurrently activated dilator effect, which is again independent of FP.