Impact of chronic hyperleptinemia on placental ischemia‐induced hypertension in pregnant rats

Abstract

Obesity is a risk factor for preeclampsia, which is new‐onset hypertension during pregnancy. The mechanisms linking obesity and preeclampsia are poorly understood. The adipokine, leptin, is elevated in the circulation in proportion to fat mass and elicits hypertension when infused into non‐pregnant animals. However, less is studied about how hyperleptinemia impacts blood pressure regulation during pregnancy. A contributing factor to hypertension during preeclampsia is placental ischemia. Therefore, we tested the hypothesis that chronic hyperleptinemia exaggerates placental ischemia‐induced hypertension. On gestational day 14, timed‐pregnant Sprague‐Dawley rats were implanted with osmotic pumps to intravenously deliver recombinant rat leptin at 1.0 ug/kg per min or vehicle and placental ischemia was produced by the reduced uterine perfusion pressure (RUPP) procedure or Sham surgery. By day 19, leptin levels were elevated (P<0.05) in Sham (leptin‐infused, N=9: 41.0±2.8 ng/mL vs vehicle, N=23: 0.8±0.1 ng/mL) and RUPP (leptin‐infused, N=9: 29.7±7.2 ng/mL vs vehicle, N=17: 1.0±0.1 ng/mL). RUPP elicited hypertension (Sham+vehicle: 100±1 mmHg vs RUPP+vehicle: 122±3 mmHg mean arterial blood pressure, P<0.05). In contrast to our hypothesis, hyperleptinemia attenuated RUPP hypertension (RUPP+leptin: 109±4 mmHg, P<0.05 vs RUPP+vehicle) and did not alter blood pressure in Sham rats (Sham+leptin: 100±6 mmHg vs Sham+vehicle). Therefore, we examined whether hyperleptinemia was vasoprotective by promoting vasorelaxation during pregnancy in isolated third‐order mesenteric arteries. Although endothelial‐dependent vasorelaxation to acetylcholine (measured as logEC50 sensitivity) was similar within Sham (vehicle: −6.8±0.1 M vs leptin: −6.9±0.2 M) and RUPP (vehicle: −7.0±0.2 M vs leptin: −7.0±0.3 M) groups, endothelial‐independent vasorelaxation to the nitric oxide (NO)‐donor, sodium nitroprusside, was increased (P<0.05) in both Sham (vehicle: −6.0±0.2 M vs leptin: −6.8±0.3 M) and RUPP (vehicle: −6.9±0.2 M vs leptin: −7.6±0.01 M) groups. This suggested that NO‐cyclic guanosine monophosphate (cGMP) signaling was increased. Plasma levels of cGMP were elevated (P<0.05) within Sham (vehicle: 1.6±0.3 pmol/mL vs leptin: 3.9±0.6 pmol/mL) and RUPP (vehicle: 3.6±0.8 pmol/mL vs leptin: 5.8±1.1 pmol/mL) groups. In contrast to our original hypothesis, chronic hyperleptinemia does not produce hypertension during pregnancy likely via promoting vascular NO‐cGMP signaling.Support or Funding InformationHL130577