Restoring placental growth factor-soluble fms-like tyrosine kinase-1 balance reverses vascular hyper-reactivity and hypertension in pregnancy.
Restoring placental growth factor-soluble fms-like tyrosine kinase-1 balance reverses vascular hyper-reactivity and hypertension in pregnancy.
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DOI：
10.1152/ajpregu.00137.2016
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发表时间：
2016-09
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通讯作者：
Minglin Zhu;Zongli Ren;J. S. Possomato‐Vieira;R. Khalil
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作者：
Minglin Zhu;Zongli Ren;J. S. Possomato‐Vieira;R. Khalil
子痫前期（Preeclampsia，PE）是一种发病机制尚不清楚的妊娠期高血压疾病（Pregnancyhypertensive disorder，HTN-Preg）。抗血管生成可溶性fms样酪氨酸激酶-1（sFlt-1）和血管生成胎盘生长因子（PlGF）之间的失衡在PE中已被观察到，但涉及的血管靶点和信号通路尚不清楚。我们评估了通过降低子宫胎盘灌注压（RUPP）产生的HTN-Preg大鼠模型中sFlt-1/PlGF失衡和血管功能障碍的程度，并测试了在妊娠第14天（Preg）大鼠中通过输注sFlt-1（10 μg·kg（-1）·d（-1））诱导可比较的sFlt-1/PlGF失衡是否引起血压（BP）和血管反应性的类似升高。利用这些指导性测量，我们然后测试通过在RUPP大鼠中输注PIGF（20 μg·kg（-1）·day（-1））来恢复sFlt-1/PlGF平衡是否会改善血压和血管功能。在妊娠第19天，BP在Preg+sFlt-1和RUPP > Preg中，在RUPP +PlGF Preg中，在RUPP + PlGF RUPP中，并且被N（ω）-硝基-l-精氨酸甲酯（l-NAME）或ODQ处理或内皮去除阻断。Western印迹显示主动脉总内皮NOS（eNOS）和活化的磷酸化eNOS在Preg+sFlt-1和RUPP中表达。ACh诱导的血管硝酸盐/亚硝酸盐产生在Preg+sFlt-1和RUPP RUPP中。血管对外源性NO供体硝普钠的舒张作用在各组之间没有差异。因此，血管生成平衡向抗血管生成sFlt-1的倾斜与血管舒张减少和血管收缩和BP增加相关。使用PlGF恢复血管生成/抗血管生成平衡增强内皮NO-cGMP血管舒张，降低HTN-Preg大鼠的血管收缩和血压，并可能提供PE管理的新方法。
Preeclampsia (PE) is a pregnancy-related hypertensive disorder (HTN-Preg) with unclear mechanism. An imbalance between antiangiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) and angiogenic placental growth factor (PlGF) has been observed in PE, but the vascular targets and signaling pathways involved are unclear. We assessed the extent of sFlt-1/PlGF imbalance and vascular dysfunction in a rat model of HTN-Preg produced by reduction of uteroplacental perfusion pressure (RUPP), and tested whether inducing a comparable sFlt-1/PlGF imbalance by infusing sFlt-1 (10 μg·kg(-1)·day(-1)) in day 14 pregnant (Preg) rats cause similar increases in blood pressure (BP) and vascular reactivity. Using these guiding measurements, we then tested whether restoring sFlt-1/PlGF balance by infusing PIGF (20 μg·kg(-1)·day(-1)) in RUPP rats would improve BP and vascular function. On gestational day 19, BP was in Preg+sFlt-1 and RUPP > Preg, and in RUPP+PlGF Preg, and in RUPP+PlGF RUPP, and was blocked by N(ω)-nitro-l-arginine methyl ester (l-NAME) or ODQ treatment or endothelium removal. Western blots revealed that aortic total endothelial NOS (eNOS) and activated phosphorylated-eNOS were in Preg+sFlt-1 and RUPP RUPP. ACh-induced vascular nitrate/nitrite production was in Preg+sFlt-1 and RUPP RUPP. Vascular relaxation to the exogenous NO donor sodium nitroprusside was not different among groups. Thus, a tilt in the angiogenic balance toward anti-angiogenic sFlt-1 is associated with decreased vascular relaxation and increased vasoconstriction and BP. Restoring the angiogenic/antiangiogenic balance using PlGF enhances endothelial NO-cGMP vascular relaxation and decreases vasoconstriction and BP in HTN-Preg rats and could offer a new approach in the management of PE.