Mechanisms of thrombin-Induced myometrial contractions: Potential targets of progesterone
Mechanisms of thrombin-Induced myometrial contractions: Potential targets of progesterone
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DOI：
10.1371/journal.pone.0231944
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发表时间：
2020-05-04
期刊：
影响因子：
3.7
通讯作者：
Kondoh, Eiji
中科院分区：
文献类型：
--
作者：
Nishimura, Fumitomo;Mogami, Haruta;Kondoh, Eiji
孕期宫内出血是早产的主要危险因素。凝血酶是血液中含量最丰富的凝血因子，与子宫肌层收缩有关。在这里，我们研究了凝血酶诱导的子宫肌层收缩的分子机制和信号转导。首先，对具有代表性的宫内出血的胎盘早剥的组织学研究表明，凝血酶在浸润性出血中表达，凝血酶受体(蛋白酶激活受体1，PAR1)在出血周围的子宫肌层细胞中高表达。用凝血酶处理人子宫肌层细胞，可通过PAR1增强收缩。凝血酶诱导的肌球蛋白信号然后通过肌球蛋白轻链激酶的激活和Rho诱导的肌球蛋白轻链-2的磷酸化来介导。此外，凝血酶还能增加人子宫肌层细胞前列腺素-过氧化物酶合酶-2(Ptgs2或COX2)的mRNA和前列腺素E2和F2α的合成。凝血酶显著增加IL-1β的mRNA水平，而降低前列腺素EP3和F2α受体的表达。孕酮部分阻断凝血酶诱导的子宫肌层收缩，同时抑制凝血酶诱导的Ptgs2和IL1bmRNA表达的增加以及PAR1的表达。总而言之，凝血酶通过两种机制诱导子宫肌层收缩，包括直接激活肌球蛋白和间接增加前列腺素合成。结果提示孕酮对早产合并宫内出血有治疗潜力。
Intrauterine bleeding during pregnancy is a major risk factor for preterm birth. Thrombin, the most abundant coagulation factor in blood, is associated with uterine myometrial contraction. Here, we investigated the molecular mechanism and signaling of thrombin-induced myometrial contraction. First, histologic studies of placental abruption, as a representative intrauterine bleeding, revealed that thrombin was expressed within the infiltrating hemorrhage and that thrombin receptor (protease-activated receptor 1, PAR1) was highly expressed in myometrial cells surrounding the hemorrhage. Treatment of human myometrial cells with thrombin resulted in augmented contraction via PAR1. Thrombin-induced signaling to myosin was then mediated by activation of myosin light chain kinase- and Rho-induced phosphorylation of myosin light chain-2. In addition, thrombin increased prostaglandin-endoperoxidase synthase-2 (PTGS2 or COX2) mRNA and prostaglandin E2 and F2 alpha synthesis in human myometrial cells. Thrombin significantly increased the mRNA level of interleukine-1 beta, whereas it decreased the expressions of prostaglandin EP3 and F2 alpha receptors. Progesterone partially blocked thrombin-induced myometrial contractions, which was accompanied by suppression of the thrombin-induced increase of PTGS2 and IL1B mRNA expressions as well as suppression of PAR1 expression. Collectively, thrombin induces myometrial contractions by two mechanisms, including direct activation of myosin and indirect increases in prostaglandin synthesis. The results suggest a therapeutic potential of progesterone for preterm labor complicated by intrauterine bleeding.