Vascular endothelial growth factor Ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe Preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome
Vascular endothelial growth factor Ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe Preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome
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DOI：
10.1016/s0002-9440(10)62567-9
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发表时间：
2002-04-01
影响因子：
6
通讯作者：
Fisher, SJ
中科院分区：
文献类型：
--
作者：
Zhou, Y;McMaster, M;Fisher, SJ
人类胎盘发育结合了肿瘤发生和血管生成的因素。器官的特殊上皮细胞，称为细胞滋养层细胞，侵入子宫，它们驻留在子宫的间质中。它们还排列子宫的动脉和静脉。在侵袭过程中，外胚层来源的细胞滋养层细胞经历假性血管生成，将其黏附分子谱系转换为模拟血管细胞的黏附分子谱系。这种转化的失败伴随着妊娠并发症先兆子痫。在这里，我们使用原位和体外分析相结合的方法来表征细胞的血管内皮生长因子(VEGF)家族配体和受体的表达，这些配体和受体是传统血管生成和血管生成的关键调节因素。妊娠早期和中期的细胞滋养层细胞分化和侵袭与血管内皮生长因子受体(VEGFR)-2表达下调有关。侵袭性细胞滋养层细胞在妊娠早期表达VEGF-A、VEGF-C、胎盘生长因子(PIGF)、VEGFR-1和VEGFR-3，足月表达VEGF-A、PIGF和VEGFR-1。在体外，细胞将血管内皮生长因子-A掺入周围的细胞外基质中，分泌PlGF。我们还发现，细胞滋养层细胞对它们产生的血管内皮生长因子配体有反应。阻断配体结合显著降低血管内细胞滋养层细胞高表达的黏附分子整合素α1的表达，并增加细胞凋亡。重度子痫前期、溶血、肝酶升高、血小板减少综合征组织切片免疫组化染色显示细胞滋养细胞VEGF-A和VEGFR-1染色减弱，而PlGF染色未受影响。细胞滋养层细胞分泌的可溶性VEGFR-1在体外也增加。总而言之，这项研究的结果表明，血管内皮生长因子家族成员调节细胞滋养层细胞的存活，在严重形式的先兆子痫中，家族成员的一部分表达受到失调。
Human placental development combines elements of tumorigenesis and vasculogenesis. The organ's specialized epithelial cells, termed cytotrophoblasts, invade the uterus where they reside in the interstitial compartment. They also line uterine arteries and veins. During invasion, ectodermally derived cytotrophoblasts undergo pseudovasculogenesis, switching their adhesion molecule repertoire to mimic that of vascular cells. Failures in this transformation accompany the pregnancy complication preeclampsia. Here, we used a combination of in situ and in vitro analyses to characterize the cell's expression of vascular endothelial growth factor (VEGF) family ligands and receptors, key regulators of conventional vasculogenesis and angiogenesis. Cytotrophoblast differentiation and invasion during the first and second trimesters of pregnancy were associated with downregulation of VEGF receptor (VEGFR)-2. Invasive cytotrophoblasts in early gestation expressed VEGF-A, VEGF-C, placental growth factor (PIGF), VEGFR-1, and VEGFR-3 and, at term, VEGF-A, PIGF, and VEGFR-1. In vitro the cells incorporated VEGF-A into the surrounding extracellular matrix; PlGF was secreted. We also found that cytotrophoblasts responded to the VEGF ligands they produced. Blocking ligand binding significantly decreased their expression of integrin alpha1, an adhesion molecule highly expressed by endovascular cytotrophoblasts, and increased apoptosis. In severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome, immunolocalization on tissue sections showed that cytotrophoblast VEGF-A and VEGFR-1 staining decreased; staining for PlGF was unaffected. Cytotrophoblast secretion of the soluble form of VEGFR-1 in vitro also increased. Together, the results of this study showed that VEGF family members regulate cytotrophoblast survival and that expression of a subset of family members is dysregulated in severe forms of preeclampsia.