Abstract Body: Preeclampsia (PE) is a hypertensive disorder of pregnancy clinically characterized by hypertension and increased risk of fetal growth restriction. Elevated levels of anti-angiogenic soluble fms-like tyrosine kinase 1 (sFlt-1) is a well-known hallmark of PE. In addition, emerging clinical evidence indicates that vascular endothelial dysfunction is a mediator of PE. Although these two facets of PE are associated, whether sFlt-1 is a crucial mediator in endothelial dysfunction in PE is unknown. We previously showed that the placenta-derived hormone leptin, whose levels characteristically increase in PE patients, induces the features of PE in pregnant mice, notably endothelial dysfunction. Novel preliminary data also shows that sFlt-1 induces an increase in placental leptin production, however, what remains to be explored is whether this pathway mediates endothelial dysfunction in PE pregnant mice. Therefore, we hypothesize that in pregnant mice, sFlt-1 induces vascular endothelial dysfunction via increasing leptin production. We bred BALB/c female mice for timed pregnancy (12-14 wk old). On gestational day (GD)11, pregnant females were implanted with subcutaneous (sc.) minipumps containing either sFlt-1 (1.2 µg/day, n=5) or saline (n=6). Uterine artery resistance index (UARI) was measured at GD17 via Doppler ultrasound. At GD18, vascular reactivity was measured in 2nd-order mesenteric arteries by wire myography. Our data showed that sFlt-1 increased UARI compared to sham mice ([PSV-EDV]/PSV; Mean±SEM;0.61±0.01vs.0.45±0.01, t test, p=0.0007). In addition, sFlt-1 reduced endothelial-dependent relaxation to acetylcholine (concentration-response, 1nM-10µM, 2-way ANOVA w/RM, p<0.0001), indicating endothelial dysfunction. sFlt-1 also reduced smooth muscle relaxation responses to sodium nitroprusside (p<0.05). To test whether sFlt-1 induces leptin production, we bred BALB/c mice as described above. At GD12, mice were treated with either sFlt-1 (sc.10 µg) or saline (n=6/group). After 24 h, mice were euthanized, and plasma and subcutaneous adipose tissue were collected. Our data showed an increase in plasma leptin in sFlt-1 group (ng/mL;5.0 ±0.2 vs.2.9±0.1, t test, p<0.0001) and an upregulation in placental leptin gene expression (normalized to 18S; fold change to control; 7.8±1.8 vs.1.1±0.3, t test, p<0.05). In conclusion, our data indicates that sFlt-1 induces vascular endothelial dysfunction and increases leptin plasma levels and gene expression in preeclampsia.