Uterine artery myosin phosphatase isoform switching and increased sensitivity to SNP in a rat L-NAME model of hypertension of pregnancy
Uterine artery myosin phosphatase isoform switching and increased sensitivity to SNP in a rat L-NAME model of hypertension of pregnancy
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DOI：
10.1152/ajpcell.00285.2007
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发表时间：
2008-02-01
影响因子：
5.5
通讯作者：
Fisher, Steven A.
中科院分区：
文献类型：
--
作者：
Lu, Yuan;Zhang, Haiying;Fisher, Steven A.
妊娠和妊娠高血压 (HtP) 期间会发生剧烈的血管床特异性血流动力学变化。由于肌球蛋白磷酸酶 (MP) 是平滑肌松弛的主要效应物，也是调节血管张力的信号通路的关键靶标，因此我们假设 MP 表达在这些条件下会发生改变。 MP (MYPT1) mRNA 和蛋白质的靶向/调节亚基的丰度在没有异构体转换的晚期妊娠大鼠的子宫动脉 (UA) 中增加了 1.7 至 2.0 倍。在 HtP 模型中，长期给予 N-omega-硝基-L-精氨酸甲酯阻断一氧化氮 (NO) 合成，MYPT1 下调并转变为编码 COOH 末端亮氨酸拉链基序的剪接变体亚型。这与主 UA 及其子分支对 NO 供体药物硝普钠的血管舒张作用的敏感性增加有关。通过磷酸酶抑制剂互变霉素预处理消除了这种差异。在透化 UA 的钙钳条件下，松弛对 NO 第二信使 cGMP 的敏感性也增加，表明 MP 的活化增强。 HtP 中 MP 表达的变化在很大程度上可以通过抗高血压药物肼屈嗪治疗来预防。我们认为，MYPT1亚型转换是一种适应性反应，在妊娠高血压引发的UAs向内重塑的情况下降低血管阻力并维持子宫血流。
Dramatic and vascular bed-specific hemodynamic changes occur in pregnancy and hypertension of pregnancy (HtP). Because myosin phosphatase ( MP) is the primary effector of smooth muscle relaxation and a key target of signaling pathways that regulate vascular tone, we hypothesized that MP expression would be altered in these conditions. The abundance of the targeting/regulatory subunit of MP (MYPT1) mRNA and protein was increased 1.7- to 2.0-fold specifically in the uterine arteries (UAs) of late-pregnant rats without isoform switching. In a model of HtP in which nitric oxide (NO) synthesis is blocked by the chronic administration of N-omega-nitro-L-arginine methyl ester, MYPT1 was downregulated and switched to the splice variant isoform that codes for the COOH-terminal leucine zipper motif. This was associated with increased sensitivity of the main UA and its sub-branches to the vasorelaxant effects of the NO donor drug sodium nitroprusside. This difference was abolished by pretreatment with the phosphatase inhibitor tautomycetin. The sensitivity of relaxation to the NO second messenger cGMP was also increased under calcium-clamp conditions in permeabilized UAs, indicating heightened activation of MP. The changes in MP expression in HtP were largely prevented by treatment with the antihypertensive medicine hydralazine. We propose that MYPT1 isoform switching is an adaptive response to reduce vascular resistance and maintain uterine blood flow in the setting of hypertension-triggered inward remodeling of the UAs in hypertension of pregnancy.