Abstract P179: Placental Ischemia-Induced Hypertension is Attenuated in Melanocortin-4 Receptor (MC4R)-Deficient Pregnant Rats

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The incidence of preeclampsia (PE), a pregnancy-specific disorder of new-onset hypertension that is linked to placental ischemia, has increased over the last several decades. While obesity is a major risk factor for PE, the mechanisms whereby obesity impacts placental ischemia-induced hypertension are not fully understood. We recently reported that placental ischemia-induced hypertension is partially dependent upon an intact sympathetic nervous system (SNS). In various hypertensive models including obesity, blockade of MC4R signaling leads to increased food intake and body weight but protects against the development of hypertension via suppression of the SNS. Although blockade of MC4R may lead to increased body weight during pregnancy, we tested the hypothesis that placental ischemia-induced hypertension is attenuated in obese MC4R-deficient pregnant rats. Wild-type (WT) and MC4R heterozygous-deficient rats were mated with genotype-matched males at ~12 wks old. All rats were maintained on NIH31 chow diet. On gestational day 14, rats were subjected to chronic placental ischemia via the reduced uterine perfusion pressure (RUPP) procedure or Sham surgery. By day 19, conscious mean arterial blood pressure (MAP, carotid catheter) was elevated in RUPP WT (N=21) over Sham WT rats (N=14) (117±2 vs. 101±1 mmHg, P<0.05) with reduced average fetus (1.71±0.04 vs. 1.89±0.05 g, P<0.05) but no change in average placenta weights (0.46±0.02 vs. 0.47±0.01 g), respectively. In Sham MC4R-def vs. Sham WT, respectively, there was increased (P<0.05) body weight (366±8 vs. 337±6 g), total body fat mass (72±4 vs. 44±2 g), and circulating leptin adipokine levels (6.9±0.7 vs. 3.3±0.3 ng/mL) but with similar average fetus (1.92±0.02 vs. 1.89±0.05 g) and placenta weights (0.49±0.01 vs. 0.47±0.01 g). Even though blood pressure was elevated in Sham MC4R-def (109±2 mmHg, P<0.05) over Sham WT, the hypertensive response to RUPP was attenuated in MC4R-def rats (114±2 mmHg). RUPP did not alter leptin levels in MC4R-def rats (6.4±1 ng/mL). In conclusion, these data suggest that MC4R heterozygous-def pregnant rats are obese and have higher blood pressure during pregnancy. However, placental ischemia may require a full complement of MC4R expression to elicit a hypertensive response.