soluble FMS-like tyrosine kinase-1 induces vascular dysfunction and increases leptin production in both human placentas and mice

Preeclampsia (PE) is a hypertensive disorder of pregnancy induced by placental dysfunction and often ischemia. Elevated serum levels of soluble fms-like tyrosine kinase 1 (sFlt-1), a classic feature of PE, is associated with severe maternal-fetal outcomes and induces PE characteristics in animal models. Maternal leptin levels increase in parallel in PE patients, and recent studies by our group show leptin induces vascular endothelial dysfunction, fetal growth restriction and hypertension in murine pregnancy. However, whether the effects of sFlt-1 to induce PE involve leptin are unknown. We hypothesize sFlt-1 induces endothelial dysfunction via increasing leptin production. To test our hypothesis, 12-wk BALB/c female mice were bred in timed pregnancy and were implanted with subcutaneous minipumps containing sFlt-1 (1.2 µg/day, n=5) or saline (n=6) on gestational day (GD)11. Uterine artery resistance index (UARI) was measured via Doppler ultrasound at GD17, and we assessed vascular function in 2nd-order mesenteric arteries by wire myography at GD18. Plasma and adipose tissue were collected at baseline (BSL), GD11, GD15 and GD18 to measure plasma leptin level and leptin gene expression (qRT-PCR). Our data showed that unlike the control group, sFlt-1 infusion increased plasma leptin levels at GD18 compared to BSL (6.4±1.2 vs. 2.7±1.3 ng/mL, 1-Way ANOVA, p<0.01). Additionally, leptin gene expression at GD18 was upregulated in sFlt-1 group compared to GD11 (fold change (FC): 4.06±1.5 vs. 1.2±0.2, 1-Way ANOVA, p=0.006). UARI increased in sFlt-1 treated female mice at GD17 ([PSV-EDV]/PSV; Mean±SEM;0.61±0.01 vs. 0.45±0.01, t test, p=0.0007). Moreover, sFlt-1 impaired endothelial dependent relaxation to acetylcholine (concentration-response, 1nM-10µM, 2-way ANOVA w/RM, p<0.0001), signifying endothelial dysfunction. To test whether sFlt-1 induces leptin production in humans, we used freshly collected placental explants from normal deliveries at Wellstar MCG Health and treated them with sFlt-1(1 ng/ml, 72 h) or vehicle and measured leptin secretion in media. Our data showed an increased leptin media concentration in sFlt-1 treated placental explants compared with vehicle (FC to control 4.06±0.73, t test, p=0.01). Interestingly, the sFlt-1 induced leptin upregulation effect was reversed by adding either vascular endothelial growth factor (VEGF) or placental growth factor (PlGF) to sFlt-1 treated explants (media leptin secretion sFlt-1+VEGF vs. sFlt-1: 1.1±0.9 vs. 1.5±0.1; sFlt-1+PLGF vs. sFlt-1: 1.0±0.9 vs.1.5±0.1 pg/µg, 1-Way ANOVA, p<0.0001), indicating that VEGF receptor activation likely mediates leptin production in placenta. In conclusion, our data shows that sFlt-1 increases leptin production in both mice and humans which could be a candidate pathway mediating endothelial dysfunction and adverse maternal outcomes in PE. This work is supported by the National Institute of Health Research Grants (NIH-R01 HL169576, NIH-R00 HL146948) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.