Elgazzaz Mona, Ogbi Safia, Moronge Desmond, Mellott Elisabeth, Cooper Gibson, Backer Kristin, Hitchings Joanna, Zarate Luis Valesquez, Kavuri Sravankumar, Lee Tae Jin, Ilatovskaya Daria, Woodham Padmashree C, Maher James, Annex Brian H, Faulkner Jessica L
Department of Physiology, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.
Genetics Unit, Department of Histology and Cell Biology, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt.
bioRxiv. 2025 Jun 1:2025.05.27.656489. doi: 10.1101/2025.05.27.656489.
Heightened soluble FMS-like tyrosine kinase-1 (sFlt-1) levels is a hallmark of preeclampsia patients and induces a state of angiogenic imbalance by sequestering free vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). The receptors for VEGF and PlGF, membrane-bound VEGFR, are expressed in placental trophoblast cells, but their functions are largely unknown. Placenta production of leptin significantly increases in preeclampsia, and we recently showed leptin induces placental and vascular endothelial dysfunction in pregnancy. We hypothesized that there is a mechanistic link in which inappropriately high sFlt-1 in preeclampsia leads to an increase in trophoblast leptin production. We treated human placental explants and trophoblast cells with sFlt-1 and show an increase in leptin peptide production, which is ablated by coadministration with either VEGF or placental growth factor (PLGF). We further demonstrate that VEGFR1 and 3, not R2, expressions are predominant in human trophoblasts and that reducing activation of these receptors mediates trophoblast leptin production. In pregnant mice, we show that sFlt-1 infusion induces vascular endothelial dysfunction in association with significantly elevated plasma leptin levels. In pregnant sFlt-1-infused mice treatment with leptin receptor antagonist significantly ablated vascular endothelial dysfunction. Collectively, these data indicate that angiogenic imbalance in preeclampsia impacts placental trophoblast endocrine function by suppressing VEGFR1 and 3 activation, resulting in leptin overproduction. Furthermore, sFlt-1 induces vascular endothelial dysfunction in mice dependent on leptin receptor activation.
可溶性FMS样酪氨酸激酶-1（sFlt-1）水平升高是子痫前期患者的一个标志，它通过螯合游离的血管内皮生长因子（VEGF）和胎盘生长因子（PlGF）诱导血管生成失衡状态。VEGF和PlGF的受体，即膜结合型VEGFR，在胎盘滋养层细胞中表达，但其功能在很大程度上尚不清楚。子痫前期时胎盘瘦素的产生显著增加，我们最近发现瘦素会导致孕期胎盘和血管内皮功能障碍。我们推测子痫前期中sFlt-1过高存在一种机制联系，导致滋养层瘦素产生增加。我们用sFlt-1处理人胎盘外植体和滋养层细胞，发现瘦素肽产生增加，而与VEGF或胎盘生长因子（PLGF）共同给药可消除这种增加。我们进一步证明，VEGFR1和3而非R2在人滋养层中表达占主导，降低这些受体的激活介导滋养层瘦素产生。在怀孕小鼠中，我们发现输注sFlt-1会诱导血管内皮功能障碍，同时血浆瘦素水平显著升高。在输注sFlt-1的怀孕小鼠中，用瘦素受体拮抗剂治疗可显著消除血管内皮功能障碍。总体而言，这些数据表明子痫前期的血管生成失衡通过抑制VEGFR1和3的激活影响胎盘滋养层内分泌功能，导致瘦素过度产生。此外，sFlt-1在小鼠中诱导血管内皮功能障碍依赖于瘦素受体激活。
