Abstract Body: Preeclampsia (PE) is a hypertensive disorder of pregnancy that increases cardiometabolic risk for both mother and offspring later in life. Clinical studies persistently show that leptin levels increase in patients with PE. Our group showed that leptin infusion at mid-end of gestation induces key features of PE, including hypertension, fetal growth restriction and endothelial dysfunction in mice. However, whether elevated leptin levels during pregnancy program adverse offspring cardiometabolic health is unknown. We hypothesized that offspring born to dams infused with leptin in pregnancy show a higher proclivity to cardiovascular disease later in life. C57BL/6J females were bred for timed pregnancy (12-14 wk old). On gestational day 11, dams were implanted with osmotic pumps containing saline (XLEP) or leptin (LEP; 0.9mg/kg/day/7days). Offspring were allowed to nurse until 21 days. At 6 months of age, offspring were implanted with telemetry probes and baseline blood pressure (BP) recording initiated for one week after recovery. 1 wk later mice were put on 4% high salt diet (HSD) and angiotensin II osmotic pump (Ang-II, 490 ng/kg/min) for 7 days resulting in the following groups: XLEP+NSD, XLEP+HSD, XLEP+HSD+Ang-II, LEP+NSD, LEP+HSD, LEP+HSD+Ang-II (n=6M, 6F/group). At the end of protocol, mice were euthanized, and vascular reactivity was measured in 2nd order mesenteric arteries by wire myography. Our data shows that at baseline conditions, LEP mice showed no BP differences compared to XLEP mice. However, LEP+HSD+Ang-II males showed drastic elevation in BP compared to XLEP male offspring (Mean±SEM; 133±3.9 vs. 101±8.4 mean arterial pressure, respectively, p=0.003), while LEP+HSD+Ang-II females did not show BP differences compared to XLEP+HSD+Ang-II females (124.6±8 vs. 122.4±4.9 respectively, p>0.05). Furthermore, LEP+NSD males showed impaired endothelial dependent relaxation in response to acetylcholine (concentration-response, 1nM-10µM, 2-way ANOVA, p<0.0001) compared to XLEP-NSD. There were no significant differences in endothelial function of LEP female offspring compared to XLEP females (p>0.05). Collectively, our data indicates male-specific programming in hyperleptinemic pregnancies results in increased sensitivity to hypertensive stimuli and endothelial dysfunction. In conclusion, male offspring are more susceptible to long-term adverse outcomes of high leptin levels during pregnancy.