Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, China.
Emergency Department, The First Affiliated Hospital, University of South China, Hengyang, China.
J Obstet Gynaecol Res. 2024 Oct;50(10):1813-1829. doi: 10.1111/jog.16050. Epub 2024 Sep 17.
Hyperglycemia is closely related to trophoblast dysfunction during pregnancy and results in suppressed invasion, migration, and pro-inflammatory cell death of trophoblasts. Hyperglycemia is a dependent risk factor for gestational hypertension accompanied by decreased placental growth factor (PLGF), which is important for maternal and fetal development. However, there is currently a lack of evidence to support whether PLGF can alleviate trophoblast cell dysfunction caused by high blood sugar. Here, we aim to clarify the effect of hyperglycemia on trophoblast dysfunction and determine how PLGF affects this process.
The changes in placental tissue histomorphology from gestational diabetes mellitus (GDM) patients were compared with those of normal placentas. HTR8/SVneo cells were cultured in different amounts of glucose to examine cellular pyroptosis, migration, and invasion as well as PLGF levels. Furthermore, the levels of pyroptosis-related proteins (NLRP3, pro-caspase1, caspase1, IL-1β, and Gasdermin D [GSDMD]) as well as autophagy-related proteins (LC3-II, Beclin1, and p62) were examined by Western blotting. The GFP-mRFP-LC3-II system and transmission electron microscopy were used to detect mitophagy levels, and small interfering RNAs targeting BCL2 Interacting Protein 3 (siBNIP3) and PTEN-induced kinase 1 (siPINK1) were used to determine the role of mitophagy in pyroptotic death of HTR-8/SVneo cells.
Our results show that hyperglycemia upregulates NLRP3, pro-caspase1, caspase1, IL-1β at the protein level in GDM patients. High glucose (HG, 25 mM) inhibits viability, invasion, and migration of trophoblast cells while suppressing superoxide dismutase levels and promoting malondialdehyde production, thus leading to a senescence associated beta-gal-positive cell burst. PLGF levels in nucleus and the cytosol are also inhibited by HG, whereas PLGF treatment inhibited pyroptosis-related protein levels of NLRP3, pro-caspase1, caspase1, IL-1β, and GSDMD, Gasdermin D N-terminal domain (GSDMD-N). HG-induced mitochondrial dysfunction and BNIP3 and PINK1/Parkin expression. Knocking down BINP3 and PINK1 abolished the protective role of PLGF by preventing mitophagy.
PLGF inhibited hyperglycemia, while PLGF reversed hyperglycemic injury by promoting mitophagy via the BNIP3/PINK1/Parkin pathway. Altogether, these results suggest that PLGF may protect against trophoblast dysfunction in diabetes.
怀孕期间的高血糖与滋养层功能障碍密切相关，导致滋养层细胞侵袭、迁移和促炎细胞死亡减少。高血糖是妊娠高血压的一个依赖风险因素，同时伴有胎盘生长因子（PLGF）减少，PLGF 对母婴发育很重要。然而，目前尚无证据表明 PLGF 是否能缓解高血糖引起的滋养层细胞功能障碍。在这里，我们旨在阐明高血糖对滋养层功能障碍的影响，并确定 PLGF 如何影响这一过程。
比较了来自妊娠糖尿病（GDM）患者的胎盘组织组织形态学变化与正常胎盘的变化。在不同浓度的葡萄糖下培养 HTR8/SVneo 细胞，检测细胞细胞焦亡、迁移和侵袭以及 PLGF 水平。此外，通过 Western blot 检测焦亡相关蛋白（NLRP3、pro-caspase1、caspase1、IL-1β和 Gasdermin D [GSDMD]）和自噬相关蛋白（LC3-II、Beclin1 和 p62）的水平。使用 GFP-mRFP-LC3-II 系统和透射电子显微镜检测线粒体自噬水平，并用 BCL2 相互作用蛋白 3（siBNIP3）和 PTEN 诱导激酶 1（siPINK1）的小干扰 RNA 确定线粒体自噬在 HTR-8/SVneo 细胞焦亡中的作用。
我们的结果表明，高血糖上调了 GDM 患者 NLRP3、pro-caspase1、caspase1、IL-1β 蛋白水平。高葡萄糖（HG，25mM）抑制滋养层细胞活力、侵袭和迁移，同时降低超氧化物歧化酶水平并促进丙二醛产生，从而导致衰老相关β-半乳糖阳性细胞爆发。核和细胞质中的 PLGF 水平也受到 HG 的抑制，而 PLGF 处理抑制了 NLRP3、pro-caspase1、caspase1、IL-1β 和 GSDMD-N 等焦亡相关蛋白的表达。HG 诱导的线粒体功能障碍和 BNIP3 和 PINK1/Parkin 的表达。敲低 BNIP3 和 PINK1 通过阻止线粒体自噬消除了 PLGF 的保护作用。
PLGF 抑制高血糖，而 PLGF 通过 BNIP3/PINK1/Parkin 通路促进线粒体自噬来逆转高血糖损伤。总之，这些结果表明 PLGF 可能对糖尿病中的滋养层功能障碍具有保护作用。
