While obesity is a major risk factor for preeclampsia, the mechanisms linking obesity and hypertension during preeclampsia are unclear. Hypertension in preeclampsia is associated with placental ischemia-induced release of factors such as anti-angiogenic sFlt-1 into the maternal circulation, which antagonizes vascular endothelial growth factor (VEGF) and endothelial function. The purpose of this study was to determine the effect of obesity on angiogenic factors and endothelial function in obese melanocortin 4 receptor (MC4R) knockout rats (MC4R+/-, n=4-9) and lean control MC4R+/+ rats (n=4-8). Pre-pregnancy body weight (298±6 vs. 266±3g) and total body fat mass (EchoMRI: 56±3 vs. 44±1g) was greater (P<0.05) in MC4R+/- vs. MC4R+/+ at 15 weeks old when timed-pregnant rats were generated. At gestational day (GD) 18, body weight (362±6 vs. 336±5g) and total body fat mass (62±6 vs. 45±5g) were greater (P<0.05) in MC4R+/- and MC4R+/+ pregnant rats, respectively. Mean arterial blood pressure (indwelling carotid catheter) was similar in MC4R+/- (113±4mmHg) and MC4R+/+ (109±4mmHg) rats. Plasma sFlt-1 was not significantly elevated in MC4R+/- vs. MC4R+/+ (228±86 vs. 141±53 pg/mL). Interestingly, VEGF was greater in the obese pregnant rats (4091±336 vs. 2854±475pg/mL, P<0.05). Wire myography demonstrated in third-order mesenteric arteries that sensitivity (logEC50) to acetylcholine (endothelial dependent)-induced vasorelaxation (-11.4±0.7 vs. -6.9±0.7M, P<0.05) and sodium nitroprusside (exogenous nitric oxide donor) (-8.3±0.1 vs. -7.5±0.2M, P<0.05) was greater in obese MC4R+/- vs. lean MC4R+/+ pregnant rats. These data indicate that during normal pregnancy, obesity is associated with greater circulating VEGF levels and nitric oxide-dependent vasorelaxation in resistance arteries. Because soluble factors from the ischemic placenta target and reduce nitric oxide bioavailability, we propose that the hypertensive and endothelial dysfunction responses to reductions in uterine perfusion may be exaggerated in obese pregnant animals.