Program in Development and Fetal Health, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada.
J Thromb Haemost. 2011 Dec;9(12):2486-97. doi: 10.1111/j.1538-7836.2011.04526.x.
Severe preeclampsia is characterized by hypertension, renal injury and placental dysfunction. Prothrombotic disorders are discovered in 10-20% of women with preeclampsia, providing the rationale for prescribing low-molecular-weight heparin (LMWH) in future pregnancies. Heparin has diverse molecular actions and appears to reduce the recurrence risk of preeclampsia in women without prothrombotic disorders. The placenta-derived anti-angiogenic splice-variant protein soluble vascular endothelial growth factor (VEGF) receptor-1 (sFLT1) is strongly implicated in the pathogenesis of the underlying endothelial dysfunction. As the placental syncytiotrophoblast is the principal source of sFLT1, we tested the hypothesis that heparin suppresses placental sFLT1 secretion.
First trimester placental villi exposed to LMWH (0.25-25 IU mL(-1)) in an in vitro explant model significantly increased the expression and release of sFLT1 by the syncytiotrophoblast into culture media, reducing phosphorylation of FLT1 and KDR receptors in cultured human umbilical vein endothelial cells. This response was significantly diminished in placental villi from healthy term pregnancies. Placental villi from severely preeclamptic pregnancies had a higher baseline sFLT1 release, compared with first trimester placental villi and did not respond to LMWH treatment. LMWH promoted villous cytotrophoblast proliferation (BrdU incorporation) and impaired syncytial fusion-differentiation, causing syncytiotrophoblast apoptosis (by caspase 3&7 activity and TUNEL staining) and necrosis (ADP/ATP ratio).
LMWH promotes sFLT1 synthesis and release from first trimester placental villi in a manner similar to that of severely preeclamptic placental villi, which antagonizes VEGF signaling in endothelial cells. These effects in part are mediated by an interaction between heparin and the cytotrophoblasts that regenerates the overlying syncytiotrophoblast responsible for sFLT1 secretion into the maternal blood.
重度子痫前期的特征是高血压、肾脏损伤和胎盘功能障碍。10-20%的子痫前期妇女存在血栓前状态，这为低分子肝素（LMWH）在未来妊娠中的应用提供了依据。肝素具有多种分子作用，似乎可以降低无血栓前状态妇女子痫前期的复发风险。胎盘来源的抗血管生成剪接变异蛋白可溶性血管内皮生长因子（VEGF）受体-1（sFLT1）强烈提示其与内皮功能障碍的发病机制有关。由于胎盘合体滋养层是 sFLT1 的主要来源，我们检验了肝素抑制胎盘 sFLT1 分泌的假说。
在体外器官培养模型中，将低分子肝素（0.25-25 IU/ml）作用于第一孕期胎盘绒毛，显著增加合体滋养层向培养基中 sFLT1 的表达和释放，减少培养的人脐静脉内皮细胞中 FLT1 和 KDR 受体的磷酸化。该反应在健康足月妊娠胎盘绒毛中明显减弱。与第一孕期胎盘绒毛相比，重度子痫前期妊娠胎盘绒毛的基础 sFLT1 释放量较高，且对 LMWH 治疗无反应。LMWH 促进绒毛滋养层细胞增殖（BrdU 掺入），损害合胞体融合-分化，导致合体滋养层细胞凋亡（通过 caspase 3&7 活性和 TUNEL 染色）和坏死（ADP/ATP 比值）。
LMWH 以类似于重度子痫前期胎盘绒毛的方式促进第一孕期胎盘绒毛中 sFLT1 的合成和释放，拮抗内皮细胞中 VEGF 信号。这些作用部分是通过肝素与滋养细胞相互作用介导的，滋养细胞再生负责将 sFLT1 分泌到母体血液中的合体滋养层。
