在严重子痫前期发病过程中，抑制 HIF-1a 介导的 TLR4 激活可减少胎盘微血管内皮细胞的凋亡并促进其血管生成。
Inhibition of HIF-1a-mediated TLR4 activation decreases apoptosis and promotes angiogenesis of placental microvascular endothelial cells during severe pre-eclampsia pathogenesis.
机构信息
Department of Obstetrics, Guangdong Woman and Children Hospital, Guangzhou, Guangdong, China.
Department of Obstetrics, Guangdong Woman and Children Hospital, Guangzhou, Guangdong, China.
出版信息
Placenta. 2019 Aug;83:8-16. doi: 10.1016/j.placenta.2019.06.375. Epub 2019 Jun 15.
OBJECTIVE
Hypoxia-induced factor 1a (HIF-1a) and Toll-like receptor 4 (TLR4) are involved in pre-eclampsia (PE) pathogenesis. However, little is known about their relationships. This study aimed to investigate the interaction of HIF-1a and TLR4 in PE pathogenesis.
METHODS
The expression of HIF-1a and TLR4 were analyzed by qRT-PCR. Celluar PE model was established by hypoxia/reoxygenation treatment of human placental microvascular endothelial cells (hPMEC). Cell proliferation, apoptosis, invasion and migration were analyzed by CCK-8, flow cytometry, Transwell and scratch adhesion test, respectively. Angiogenesis was performed by tube formation, Ang-1 in culture supernatant was analyzed by ELISA.
RESULTS
HIF-1a and TLR4 expression were significantly elevated in placental tissues from early-onset and late-onset severe pre-eclampsia patients compared with control, with increased Bax, TRIF and PUMA, and decreased Bcl-2 and VEGFA; Down-regulation of HIF-1a expression decreased TLR4 expression, promoted proliferation, invasion, migration and angiogenesis but suppressed apoptosis in cellular model. In addition, silencing HIF-1a and TAK232 treatment synergically promoted some more proliferation, invasion, migration and angiogenesis but suppressed apoptosis in cellular model.
CONCLUSION
HIF-1a could promote hPMEC apoptosis by regulating TLR4 expression during PE pathogenesis.
目的
缺氧诱导因子 1a（HIF-1a）和 Toll 样受体 4（TLR4）参与子痫前期（PE）的发病机制。然而，它们之间的关系知之甚少。本研究旨在探讨 HIF-1a 和 TLR4 在 PE 发病机制中的相互作用。
方法
采用 qRT-PCR 分析 HIF-1a 和 TLR4 的表达。通过缺氧/复氧处理人胎盘微血管内皮细胞（hPMEC）建立细胞性 PE 模型。采用 CCK-8 法、流式细胞术、Transwell 法和划痕黏附试验分别分析细胞增殖、凋亡、侵袭和迁移，采用 ELISA 法分析培养上清液中 Ang-1 的含量。
结果
与对照组相比，早发型和晚发型重度子痫前期患者胎盘组织中 HIF-1a 和 TLR4 的表达明显升高，Bax、TRIF 和 PUMA 增加，Bcl-2 和 VEGFA 减少；下调 HIF-1a 表达可降低 TLR4 表达，促进细胞模型的增殖、侵袭、迁移和血管生成，但抑制细胞模型的凋亡。此外，沉默 HIF-1a 和 TAK232 治疗协同促进细胞模型中更多的增殖、侵袭、迁移和血管生成，但抑制凋亡。
结论
在 PE 发病机制中，HIF-1a 可通过调节 TLR4 的表达促进 hPMEC 凋亡。
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