RGS2 squelches vascular Gi/o and Gq signaling to modulate myogenic tone and promote uterine blood flow.
RGS2 squelches vascular Gi/o and Gq signaling to modulate myogenic tone and promote uterine blood flow.
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DOI：
10.14814/phy2.12692
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发表时间：
2016-02
影响因子：
2.5
通讯作者：
Osei-Owusu P
中科院分区：
文献类型：
--
作者：
Jie L;Owens EA;Plante LA;Fang Z;Rensing DT;Moeller KD;Osei-Owusu P
子宫动脉血流（UABF）对于维持非妊娠状态下的子宫灌注以及妊娠期间子宫胎盘向胎儿输送营养和氧气至关重要。UABF受损与不孕症和几种妊娠并发症有关，包括胎儿生长受限、小于胎龄儿和先兆子痫。异常UABF的病因尚不清楚。在这里，我们确定了RGS 2（Gq/11和Gi/o G类蛋白的GTT蛋白激活蛋白）的缺乏或缺失是否会影响非妊娠小鼠的UABF。我们使用多普勒超声检查来评估野生型（WT）、Rgs 2杂合子（Rgs 2 +/−）和纯合子敲除（Rgs 2 −/−）小鼠的UABF。视频显微镜用于子宫动脉肌源性张力的离体检查，fura-2成像用于内部储存Ca 2+释放的体外评估。我们发现，Rgs 2 −/−小鼠的基线UABF速度显著降低，而阻抗测量为阻力指数（WT = 0.58 ± 0.04 vs. Rgs 2 −/− = 0.71 ± 0.03，P < 0.01）和搏动指数（WT = 0.90 ± 0.06 vs. Rgs 2 −/− = 1.25 ± 0.11，P < 0.01）增加。Rgs 2 +/−和Rgs 2 −/−小鼠的子宫动脉张力增加，在Gi/o和Gq失活后将其标准化为WT水平。相反，阻断兰尼碱受体可使WT肌源性张力增加至RGS 2突变体水平。这些数据共同表明，RGS 2缺乏至少部分地通过延长G蛋白活化通过增加肌源性张力来降低UABF。降低血管RGS 2表达的突变可能是子宫血流减少的易感因素。因此，靶向G蛋白信号传导可能会改善子宫和子宫胎盘灌注不足疾病。
Uterine artery blood flow (UABF) is critical to maintaining uterine perfusion in nonpregnant states and for uteroplacental delivery of nutrients and oxygen to the fetus during pregnancy. Impaired UABF is implicated in infertility and several pregnancy complications including fetal growth restriction, small for gestational age, and preeclampsia. The etiology of abnormal UABF is not known. Here, we determined whether deficiency or loss of RGS2, a GTPase‐activating protein for Gq/11 and Gi/o class G proteins, affects UABF in nonpregnant mice. We used Doppler ultrasonography to assess UABF in wild type (WT), Rgs2 heterozygous (Rgs2+/−), and homozygous knockout (Rgs2−/−) mice. Video microscopy was used for ex vivo examination of uterine artery myogenic tone and fura‐2 imaging for in vitro assessment of internal stores Ca2+ release. We found that baseline UABF velocity was markedly decreased while impedance measured as resistive index (WT = 0.58 ± 0.04 vs. Rgs2−/− = 0.71 ± 0.03, P < 0.01) and pulsatile index (WT = 0.90 ± 0.06 vs. Rgs2−/− = 1.25 ± 0.11, P < 0.01) was increased in Rgs2−/− mice. Uterine artery tone was augmented in Rgs2+/− and Rgs2−/− mice, which was normalized to WT levels following Gi/o and Gq inactivation. Conversely, blockade of ryanodine receptors increased WT myogenic tone to RGS2 mutant levels. The data together indicate that RGS2 deficiency decreases UABF by increasing myogenic tone at least partly through prolonged G protein activation. Mutations that decrease vascular RGS2 expression may be a predisposition to decreased uterine blood flow. Targeting G protein signaling therefore might improve uterine and uteroplacental underperfusion disorders.