Inhibition of HIF-1a-mediated TLR4 activation decreases apoptosis and promotes angiogenesis of placental microvascular endothelial cells during severe pre-eclampsia pathogenesis

• Published in: Placenta (Eastbourne) 2019-08, Vol.83, p.8-16
• Main Authors: Zhao, Lina, Ma, Ruixia, Zhang, Li, Yuan, Xiaolan, Wu, Jinhua, He, Lirong, Liu, Guocheng, Du, Rui
• Format: Article
• Language: English
• Subjects: HIF-1a; Placental microvascular endothelial cell; Preeclampsia; TLR4 signaling
• ISSN: 0143-4004; 1532-3102
• DOI: 10.1016/j.placenta.2019.06.375

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. 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. 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. HIF-1a could promote hPMEC apoptosis by regulating TLR4 expression during PE pathogenesis. •HIF-1a and TLR4 expression were significantly elevated in placental tissues.•Inhibition of HIF-1a-mediated TLR4 activation decreases apoptosis and promotes angiogenesis.•HIF-1a could promote hPMEC apoptosis by regulating TLR4 expression during PE pathogenesis.