Background:Patients with preeclampsia demonstrate increases in placental leptin production in midgestation, and an associated increase in late gestation plasma leptin levels. The consequences of mid-late gestation increases in leptin production in pregnancy is unknown. Our previous work indicates that leptin infusion induces endothelial dysfunction in nonpregnant female mice via leptin-mediated aldosterone production and endothelial mineralocorticoid receptor (ECMR) activation, which is ablated by ECMR deletion. Therefore, we hypothesized that leptin infusion in mid-gestation of pregnancy induces endothelial dysfunction and hypertension, hallmarks of clinical preeclampsia, which are prevented by ECMR deletion.Methods:Leptin was infused via miniosmotic pump (0.9 mg/kg per day) into timed-pregnant ECMR-intact (WT) and littermate-mice with ECMR deletion (KO) on gestation day (GD)11-18.Results:Leptin infusion decreased fetal weight and placental efficiency in WT mice compared with WT+vehicle. Radiotelemetry recording demonstrated that blood pressure increased in leptin-infused WT mice during infusion. Leptin infusion reduced endothelial-dependent relaxation responses to acetylcholine (ACh) in both resistance (second-order mesenteric) and conduit (aorta) vessels in WT pregnant mice. Leptin infusion increased placental ET-1 (endothelin-1) production evidenced by increased PPET-1 (preproendothelin-1) and ECE-1 (endothelin-converting enzyme-1) expressions in WT mice. Adrenal aldosterone synthase (CYP11B2) and angiotensin II type 1 receptor b (AT1Rb) expression increased with leptin infusion in pregnant WT mice. KO pregnant mice demonstrated protection from leptin-induced reductions in pup weight, placental efficiency, increased BP, and endothelial dysfunction.Conclusions:Collectively, these data indicate that leptin infusion in midgestation induces endothelial dysfunction, hypertension, and fetal growth restriction in pregnant mice, which is ablated by ECMR deletion.

中文翻译：

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妊娠中期瘦素输注可诱发小鼠临床先兆子痫的特征，该特征可通过内皮盐皮质激素受体缺失而消除

背景：先兆子痫患者在妊娠中期表现出胎盘瘦素产生增加，并且妊娠晚期血浆瘦素水平相应增加。妊娠中后期瘦素产生增加的后果尚不清楚。我们之前的工作表明，瘦素输注通过瘦素介导的醛固酮生成和内皮盐皮质激素受体（ECMR）激活，诱导非妊娠雌性小鼠内皮功能障碍，而 ECMR 缺失可消除这种功能障碍。因此，我们假设妊娠中期注射瘦素会引起内皮功能障碍和高血压，这是子痫前期的临床标志，而 ECMR 缺失可以预防这种情况。 方法：通过微渗泵（0. 每天 9 毫克/千克）在妊娠日 (GD)11-18 注入计时妊娠 ECMR 完整 (WT) 和 ECMR 缺失 (KO) 同窝小鼠。结果：瘦素输注降低了 WT 小鼠的胎儿体重和胎盘效率与WT+车辆相比。无线电遥测记录表明，注射瘦素的 WT 小鼠在输注过程中血压升高。瘦素输注可降低 WT 妊娠小鼠的阻力血管（二级肠系膜）和导管血管（主动脉）中对乙酰胆碱 (ACh) 的内皮依赖性松弛反应。瘦素输注增加了 WT 小鼠中胎盘 ET-1（内皮素-1）的产生，这通过增加 PPET-1（前内皮素原-1）和 ECE-1（内皮素转换酶-1）表达来证明。肾上腺醛固酮合酶（与 WT+载体相比，瘦素输注降低了 WT 小鼠的胎儿体重和胎盘效率。无线电遥测记录表明，注射瘦素的 WT 小鼠在输注过程中血压升高。瘦素输注可减少 WT 妊娠小鼠阻力血管（二级肠系膜）和导管（主动脉）血管中对乙酰胆碱 (ACh) 的内皮依赖性松弛反应。瘦素输注增加了 WT 小鼠中胎盘 ET-1（内皮素-1）的产生，这通过增加 PPET-1（前内皮素原-1）和 ECE-1（内皮素转换酶-1）表达来证明。肾上腺醛固酮合酶（与 WT+载体相比，瘦素输注降低了 WT 小鼠的胎儿体重和胎盘效率。无线电遥测记录表明，注射瘦素的 WT 小鼠在输注过程中血压升高。瘦素输注可降低 WT 妊娠小鼠的阻力血管（二级肠系膜）和导管血管（主动脉）中对乙酰胆碱 (ACh) 的内皮依赖性松弛反应。瘦素输注增加了 WT 小鼠中胎盘 ET-1（内皮素-1）的产生，这通过增加 PPET-1（前内皮素原-1）和 ECE-1（内皮素转换酶-1）表达来证明。肾上腺醛固酮合酶（瘦素输注可降低 WT 妊娠小鼠的阻力血管（二级肠系膜）和导管血管（主动脉）中对乙酰胆碱 (ACh) 的内皮依赖性松弛反应。瘦素输注增加了 WT 小鼠中胎盘 ET-1（内皮素-1）的产生，这通过增加 PPET-1（前内皮素原-1）和 ECE-1（内皮素转换酶-1）表达来证明。肾上腺醛固酮合酶（瘦素输注可降低 WT 妊娠小鼠的阻力血管（二级肠系膜）和导管血管（主动脉）中对乙酰胆碱 (ACh) 的内皮依赖性松弛反应。瘦素输注增加了 WT 小鼠中胎盘 ET-1（内皮素-1）的产生，这通过增加 PPET-1（前内皮素原-1）和 ECE-1（内皮素转换酶-1）表达来证明。肾上腺醛固酮合酶（CYP11B2）和血管紧张素 II 1 型受体 b（AT1Rb）的表达随着瘦素输注而增加。KO 怀孕小鼠表现出对瘦素诱导的幼仔体重、胎盘效率、血压升高和内皮功能障碍的保护作用。结论：总的来说，这些数据表明，妊娠中期输注瘦素会导致怀孕小鼠的内皮功能障碍、高血压和胎儿生长受限。 ECMR 删除消除了这一点。