Human sFLT1 Leads to Severe Changes in Placental Differentiation and Vascularization in a Transgenic hsFLT1/rtTA FGR Mouse Model
Human sFLT1 Leads to Severe Changes in Placental Differentiation and Vascularization in a Transgenic hsFLT1/rtTA FGR Mouse Model
复制标题
DOI：
10.3389/fendo.2019.00165
复制
发表时间：
2019-03-21
影响因子：
5.2
通讯作者：
Gellhaus, Alexandra
中科院分区：
文献类型：
--
作者：
Vogtmann, Rebekka;Kuehnel, Elisabeth;Gellhaus, Alexandra
抗血管生成可溶性fms样酪氨酸激酶1（sFLT 1）是先兆子痫进展中的候选者之一，通常与胎儿生长受限（FGR）相关。针对伴有/不伴有FGR的先兆子痫的治疗剂，以及用于测试此类药物的适当转基因sFLT 1小鼠模型，仍然缺失。关于sFLT 1介导的几种组织中的内皮功能障碍已经知道很多;然而，sFLT 1对胎盘和胎儿发育的影响目前尚不清楚。我们假设sFLT 1通过影响胎盘分化和血管形成参与FGR的进展，是干预策略的主要候选者。因此，我们产生了转基因诱导型人sFLT 1/反向四环素控制的反式激活因子（hsFLT 1/rtTA）小鼠，其中hsFLT 1在妊娠期间在母鼠中普遍过表达，并且根据hsFLT 1/rtTA纯合子和杂合子胎儿的遗传学。诱导hsFLT 1导致母鼠血清中hsFLT 1水平升高，所有胎盘和杂合/纯合胎仔的mRNA水平升高，导致所有足月胎仔发生FGR。在hsFLT 1/rtTA纯合子胎仔中观察到对FGR的最强影响，其表现出最高的hsFLT 1水平。仅胎儿hsFLT 1表达导致胎盘形态受损，其特征为胎盘效率降低、母体血窦扩大、胎儿毛细血管减少和胎盘分化受损，与细胞凋亡增加相关。除了受损的胎盘血管化，几种转运系统的表达，如葡萄糖转运蛋白1和3，（Glut-1; Glut-3）;氨基酸转运蛋白，溶质载体家族38，成员1和2（Slc38a1; Slc38a2）;最严重的是，hsFLT 1表达后脂肪酸转位酶Cd 36和脂肪酸结合蛋白3（Fabp 3）减少，与母体血清中磷脂的积累有关。此外，Vegf途径显示出改变，导致Vegf、Vegfb和Plgf蛋白水平降低，Bad和Caspase 9 mRNA水平升高。我们认为hsFLT 1通过减少VEGF信号传导对胎盘血管形成产生抑制作用，从而导致胎儿血管凋亡，损害胎盘分化和迷路的营养交换功能。当母体和胎儿均表达hsFLT 1并最终导致FGR并类似于人类先兆子痫表型时，这些效应更为明显。
The anti-angiogenic soluble fms-like tyrosine kinase 1 (sFLT1) is one of the candidates in the progression of preeclampsia, often associated with fetal growth restriction (FGR). Therapeutic agents against preeclampsia with/without FGR, as well as adequate transgenic sFLT1 mouse models for testing such agents, are still missing. Much is known about sFLT1-mediated endothelial dysfunction in several tissues; however, the influence of sFLT1 on placental and fetal development is currently unknown. We hypothesize that sFLT1 is involved in the progression of FGR by influencing placental differentiation and vascularization and is a prime candidate for interventional strategies. Therefore, we generated transgenic inducible human sFLT1/reverse tetracycline-controlled transactivator (hsFLT1/rtTA) mice, in which hsFLT1 is ubiquitously overexpressed during pregnancy in dams and according to the genetics in hsFLT1/rtTA homozygous and heterozygous fetuses. Induction of hsFLT1 led to elevated hsFLT1 levels in the serum of dams and on mRNA level in all placentas and hetero-/homozygous fetuses, resulting in FGR in all fetuses at term. The strongest effects in respect to FGR were observed in the hsFLT1/rtTA homozygous fetuses, which exhibited the highest hsFLT1 levels. Only fetal hsFLT1 expression led to impaired placental morphology characterized by reduced placental efficiency, enlarged maternal sinusoids, reduced fetal capillaries, and impaired labyrinthine differentiation, associated with increased apoptosis. Besides impaired placental vascularization, the expression of several transporter systems, such as glucose transporter 1 and 3 (Glut-1; Glut-3); amino acid transporters, solute carrier family 38, member one and two (Slc38a1; Slc38a2); and most severely the fatty acid translocase Cd36 and fatty acid binding protein 3 (Fabp3) was reduced upon hsFLT1 expression, associated with an accumulation of phospholipids in the maternal serum. Moreover, the Vegf pathway showed alterations, resulting in reduced Vegf, Vegfb, and Plgf protein levels and increased Bad and Caspase 9 mRNA levels. We suggest that hsFLT1 exerts an inhibitory influence on placental vascularization by reducing Vegf signaling, which leads to apoptosis in fetal vessels, impairing placental differentiation, and the nutrient exchange function of the labyrinth. These effects were more pronounced when both the dam and the fetus expressed hsFLT1 and ultimately result in FGR and resemble the preeclamptic phenotype in humans.