Arteriosclerosis, thrombosis, and vascular biology · 2026
Vascular Endothelial Growth Factor Receptors 1 and 3 Mediate Placental Trophoblast Leptin Production in Preeclampsia, Inducing Vascular Dysfunction.
СтатьяНазвание и аннотация: Перевод в очереди
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Elgazzaz Mona, Ogbi Safia, Moronge Desmond, Mellott Elisabeth, Cooper Gibson, Backer Kristin, Brawley Amalia, Hernendez Gabrielle, Hitchings Joanna, Valesquez Zarate Luis, Kavuri Sravankumar, Lee Tae Jin, Ilatovskaya Daria V, Woodham Padmashree C, Maher James, Annex Brian H, Faulkner Jessica L
Аннотация
BACKGROUND: Heightened sFlt-1 (soluble FMS-like tyrosine kinase-1) level is a hallmark of preeclampsia patients and induces a state of angiogenic imbalance by sequestering free VEGF (vascular endothelial growth factor) and PlGF (placental growth factor). The receptors for VEGF and PlGF, membrane-bound VEGFR (VEGF receptor), are expressed in placental trophoblast cells, but their functions in this cell type are largely unknown. Placental production of leptin significantly increases in preeclampsia, and we recently showed that leptin induces placental and vascular endothelial dysfunction in pregnancy. We hypothesized that inappropriately high sFlt-1 in preeclampsia leads to an increase in trophoblast leptin production.
METHODS: We treated human placental explants, trophoblast, and adipose cells with sFlt-1. We also infused pregnant mice with sFlt-1 via osmotic minipump from mid-late gestation.
RESULTS: We show an increase in leptin peptide production, which is ablated by coadministration with either VEGF or PlGF (placental growth factor). 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 a leptin receptor antagonist significantly ablated vascular endothelial dysfunction.
CONCLUSIONS: 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.
METHODS: We treated human placental explants, trophoblast, and adipose cells with sFlt-1. We also infused pregnant mice with sFlt-1 via osmotic minipump from mid-late gestation.
RESULTS: We show an increase in leptin peptide production, which is ablated by coadministration with either VEGF or PlGF (placental growth factor). 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 a leptin receptor antagonist significantly ablated vascular endothelial dysfunction.
CONCLUSIONS: 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.