Melanocortin-4 Receptor Deficiency Attenuates Placental Ischemia-Induced Hypertension in Pregnant Rats

Abstract

Preeclampsia (PE) is a pregnancy-specific disorder of new-onset hypertension linked to placental ischemia. While obesity is a major risk factor for PE, not all obese pregnant women develop pregnancy-induced hypertension or PE. Previously, we reported that placental ischemia-induced hypertension is dependent upon intact signaling of the sympathetic nervous system (SNS). Moreover, in various models of obesity, blockade of melanocortin-4 receptor (MC4R) signaling protects against the development of hypertension via suppression of the SNS. Less is known regarding this pathway during obese pregnancy. 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. On gestational day (GD) 14, MC4R wild type (WT) or heterozygous-deficient (MC4R-def) rats were subjected to chronic placental ischemia via the reduced uterine perfusion pressure (RUPP) procedure or Sham surgery then examined on GD19. In Sham MC4R-def vs. Sham WT pregnant rats, there was increased body weight, fat mass, and circulating leptin levels but they had similar fetus weights. RUPP reduced fetus weights in both strains. RUPP increased blood pressure in WT rats but this response was significantly attenuated in MC4R-def rats, even though blood pressure was elevated in Sham MC4R-def over Sham WT. These data indicate that while obese MC4R-def pregnant rats have higher blood pressure during pregnancy, placental ischemia-induced hypertension is attenuated in obese MC4R-def pregnant rats. Thus, obese women with abnormal MC4R signaling may be less susceptible to the development of placental ischemia-induced hypertension.

Melanocortin-4 Receptors and Sympathetic Nervous System Activation in Hypertension

“…MC4R activation also appears to contribute to hypertension observed in an experimental model of pre-eclampsia induced by placental ischemia [22]; in pregnant MC4R heterozygous dams submitted to placental ischemia, the rise in BP was significantly attenuated compared with wild-type pregnant controls with placental ischemia [22]. In a fetal programming model of hypertension associated with increased SNS activity, alterations in the perinatal environment have been suggested to alter MC4R activity in the offspring.…”

Administration of recombinant human placental growth factor decreases blood pressure in obese hypertensive pregnant rats

“…All rats were maintained on standard chow diet (Envigo 7013/NIH31; Indianapolis, IN, USA) and water ad libitum. At weaning (3 weeks old), offspring were placed on NIH31 diet and tail biopsies were collected for genotyping as previously described [14].…”

“…The immediate and long-term deleterious outcomes for hypertensive pregnancies and their increasing incidence call for more basic research in this area. Focusing on obesity and blood pressure regulation in pregnancy is important, as obesity is associated with increased risk for all types of hypertensive disorders of pregnancy [10][11][12][13][14].…”

Angiogenesis, Lymphangiogenesis, and the Immune Response in South African Preeclamptic Women Receiving HAART

“…Furthermore, hypoxia-inducible factor-1 (HIF-1) plays an important role in the pathogenesis of PE, and indirectly enhances the molecular regulation of VEGF [66,67,77]. The upregulated HIF-1 gene plays a critical role in the pathogenesis of PE [58,78,79,80] and contributes to the lymphangiogenesis in PE.…”