Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfimction, hypertension, and proteinuria in preeclampsia
Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfimction, hypertension, and proteinuria in preeclampsia
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DOI：
10.1172/jci200317189
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发表时间：
2003-03-01
影响因子：
15.9
通讯作者：
Karumanchi, SA
中科院分区：
文献类型：
--
作者：
Maynard, SE;Min, JY;Karumanchi, SA
先兆子痫是一种影响5%妊娠的综合征，导致大量孕产妇和胎儿发病率和死亡率。子痫前期的病理生理机制在很大程度上仍然是未知的。据推测，胎盘缺血是一个早期事件，导致胎盘产生一种或多种可溶性因子，引起母体内皮功能障碍，导致高血压、蛋白尿和水肿等临床表现。在这里，我们证实胎盘可溶性纤维样酪氨酸激酶1 (sFlt1)，一种VEGF和胎盘生长因子（PIGF）的拮抗剂，在子痫前期上调，导致sFlt1的全身水平升高，并在分娩后下降。我们证明子痫前期患者循环sFlt1增加与游离VEGF和PIGF循环水平降低相关，导致体外内皮功能障碍，可通过外源性VEGF和PIGF来挽救。此外，VEGF和PlGF在体外可引起大鼠肾小动脉微血管松弛，该松弛被sFlt1阻断。最后，给妊娠大鼠注射sFlt1诱导高血压、蛋白尿和肾小球内皮增生，这是子痫前期的典型病变。这些观察结果表明，过量的循环sFIt1有助于先兆子痫的发病机制。
Preeclampsia, a syndrome affecting 5% of pregnancies, causes substantial maternal and fetal morbidity and mortality. The pathophysiology of preeclampsia remains largely unknown. It has been hypothesized that placental ischemia is an early event, leading to placental production of a soluble factor or factors that cause maternal endothelial dysfunction, resulting in the clinical findings of hypertension, proteinuria, and edema. Here, we confirm that placental soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of VEGF and placental growth factor (PIGF), is upregulated in preeclampsia, leading to increased systemic levels of sFlt1 that fall after delivery. We demonstrate that increased circulating sFlt1 in patients with preeclampsia is associated with decreased circulating levels of free VEGF and PIGF, resulting in endothelial dysfunction in vitro that can be rescued by exogenous VEGF and PIGF. Additionally, VEGF and PlGF cause microvascular relaxation of rat renal arterioles in vitro that is blocked by sFlt1. Finally, administration of sFlt1 to pregnant rats induces hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia. These observations suggest that excess circulating sFIt1 contributes to the pathogenesis of preeclampsia.