Liu Lei, Wang Rencheng, Xu Ran, Chu Yuening, Gu Weirong
Department of Obstetrics, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China.
Department of Obstetrics and Gynecology, Renhe Hospital, Shanghai, Baoshan District 200431, China.
Pharmacol Res. 2022 Mar;177:106127. doi: 10.1016/j.phrs.2022.106127. Epub 2022 Feb 10.
Preeclampsia is a severe complication of pregnancy characterised by variable degrees of placental malperfusion. A growing body of evidence indicates that soluble endoglin and soluble fms-like tyrosine kinase-1 (sFlt-1) play important pathophysiological roles in preeclampsia, causing endothelial dysfunction, hypertension, and multiorgan injury. A drug that is safe in pregnancy and inhibits placental sFlt-1 and soluble endoglin secretion would be an attractive treatment strategy for preeclampsia. Procyanidin B2, a bioactive food compound, has been reported to exert multiple beneficial functions. Placental explant cultures in vitro are useful for studying tissue functions including release of secretory components, pharmacology, toxicology, and disease processes. The reduced uterine perfusion pressure (RUPP) rat model has been widely used as a model of preeclampsia. We aimed to investigate the effect of procyanidin B2 on preeclampsia via using placental explant cultures and RUPP rat model. In this study, we demonstrated that procyanidin B2 reduced soluble endoglin and sFlt-1 secretion from human umbilical vein endothelial cells (HUVECs), primary trophoblasts, and placental explants from preeclamptic pregnancies. Moreover, procyanidin B2 alleviated endothelial dysfunction and impaired angiogenesis induced by sFlt-1, including increasing the migration, invasion and angiogenesis of endothelial cells and decreasing the expression of vascular cell adhesion molecule-1 (VCAM-1) and leukocyte adhesion on HUVECs. In addition, procyanidin B2 promoted nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear accumulation and induced peroxisome proliferator-activated receptor γ (PPARγ) expression in primary placental tissues and endothelial cells. Importantly, Nrf2 specifically binds to the PPARγ promoter region (-1227/-1217) and enhances its transcriptional activity. Procyanidin B2 inhibits sFlt-1 secretion via the Nrf2/PPARγ axis. In the RUPP rat model of preeclampsia, procyanidin B2 attenuated RUPP-induced maternal angiogenic imbalance, hypertension and improved placental and foetal weight. Taken together, our results demonstrate that procyanidin B2 inhibits sFlt-1 secretion and ameliorates endothelial dysfunction and impaired angiogenesis via the Nrf2/PPARγ axis in preeclampsia. Procyanidin B2 may be a novel therapeutic agent for treatment of preeclampsia.
子痫前期是一种严重的妊娠并发症，其特征为不同程度的胎盘灌注不良。越来越多的证据表明，可溶性内皮糖蛋白和可溶性fms样酪氨酸激酶-1（sFlt-1）在子痫前期中发挥重要的病理生理作用，导致内皮功能障碍、高血压和多器官损伤。一种在孕期安全且能抑制胎盘sFlt-1和可溶性内皮糖蛋白分泌的药物将是子痫前期颇具吸引力的治疗策略。原花青素B2是一种生物活性食品化合物，据报道具有多种有益功能。体外胎盘外植体培养有助于研究组织功能，包括分泌成分的释放、药理学、毒理学和疾病过程。降低子宫灌注压（RUPP）大鼠模型已被广泛用作子痫前期模型。我们旨在通过使用胎盘外植体培养和RUPP大鼠模型来研究原花青素B2对子痫前期的影响。在本研究中，我们证明原花青素B2可减少人脐静脉内皮细胞（HUVECs）、原代滋养层细胞以及子痫前期妊娠胎盘外植体中可溶性内皮糖蛋白和sFlt-1的分泌。此外，原花青素B2可减轻sFlt-1诱导的内皮功能障碍和血管生成受损，包括增加内皮细胞的迁移、侵袭和血管生成，以及降低血管细胞黏附分子-1（VCAM-1）的表达和HUVECs上白细胞的黏附。此外，原花青素B2可促进原代胎盘组织和内皮细胞中核因子红细胞2相关因子2（Nrf2）的核积累并诱导过氧化物酶体增殖物激活受体γ（PPARγ）的表达。重要的是，Nrf2特异性结合PPARγ启动子区域（-1227/-1217）并增强其转录活性。原花青素B2通过Nrf2/PPARγ轴抑制sFlt-1分泌。在子痫前期的RUPP大鼠模型中，原花青素B2减轻了RUPP诱导的母体血管生成失衡、高血压，并改善了胎盘和胎儿体重。综上所述，我们的结果表明原花青素B2通过Nrf2/PPARγ轴抑制sFlt-1分泌，并改善子痫前期的内皮功能障碍和血管生成受损。原花青素B2可能是治疗子痫前期的一种新型治疗药物。
