Liu Jie, Zhao Mengmeng, Zhang Suqin, Shi Yanmei
Department of Gynecology and Obstetrics, Yantaishan Hospital, Yantai, 264001, Shandong, China.
J Mol Histol. 2025 Sep 3;56(5):290. doi: 10.1007/s10735-025-10579-0.
Pre-eclampsia (PE) is a common pregnancy complication, closely associated with endothelial dysfunction and inhibition of angiogenesis. This study aims to explore the pathological mechanisms causing endothelial dysfunction and suppressed angiogenesis in PE, with the aim of identifying potential drug targets. Human umbilical vein endothelial cells (HUVECs) were exposed to angiotensin II (Ang-II) to mimic PE-related endothelial dysfunction. Angiogenic capacity was evaluated using tube formation assay, scratch assay, flow cytometry, and CCK-8 assay. A Reduced Uterine Perfusion Pressure (RUPP) mouse model was established to recapitulate PE. Expression profiles of hypoxia-inducible factor-1α (HIF-1α), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), vascular endothelial growth factor (VEGF), placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sENG), and tumor necrosis factor-α (TNF-α) were quantified via Western blot and RT-qPCR. Biochemical assessments included levels of malondialdehyde, superoxide dismutase, glutathione, and the urine protein/creatinine (UP/cr) ratio. Systolic blood pressure was measured while placental histopathology was examined using hematoxylin and eosin (HE) staining. In HUVECs exhibiting endothelial dysfunction, ICAM-1 and VCAM-1 were markedly upregulated, whereas HIF-1α expression was significantly reduced. Overexpression of HIF-1α boosted HUVEC proliferation and migration, attenuated apoptosis and oxidative stress, enhanced expression of VEGF and PlGF, and suppressed expression of sFlt-1, sENG, and TNF-α, thereby promoting angiogenesis. In the RUPP-modeled PE mouse model, diminished HIF-1α expression coincided with elevated ICAM-1 and VCAM-1, leading to endothelial dysfunction, elevated systolic blood pressure, and increased UP/cr ratio. Conversely, HIF-1α overexpression ameliorated placental tissue damage and oxidative stress, upregulated VEGF and PlGF, downregulated sFlt-1, sENG, TNF-α, ICAM-1, and VCAM-1, and restored angiogenic capacity. HIF-1α ameliorates endothelial dysfunction in PE by suppressing the sFlt-1/sENG/TNF-α signaling pathway, thereby promoting angiogenesis and alleviating PE.
子痫前期（PE）是一种常见的妊娠并发症，与内皮功能障碍和血管生成抑制密切相关。本研究旨在探讨导致PE内皮功能障碍和血管生成受抑制的病理机制，以确定潜在的药物靶点。将人脐静脉内皮细胞（HUVECs）暴露于血管紧张素II（Ang-II）以模拟与PE相关的内皮功能障碍。使用管腔形成试验、划痕试验、流式细胞术和CCK-8试验评估血管生成能力。建立降低子宫灌注压（RUPP）小鼠模型以模拟PE。通过蛋白质免疫印迹法和逆转录-定量聚合酶链反应（RT-qPCR）对缺氧诱导因子-1α（HIF-1α）、细胞间黏附分子-1（ICAM-1）、血管细胞黏附分子-1（VCAM-1）、血管内皮生长因子（VEGF）、胎盘生长因子（PlGF）、可溶性fms样酪氨酸激酶-1（sFlt-1）、可溶性内皮糖蛋白（sENG）和肿瘤坏死因子-α（TNF-α）的表达谱进行定量分析。生化评估包括丙二醛、超氧化物歧化酶、谷胱甘肽水平以及尿蛋白/肌酐（UP/cr）比值。测量收缩压，同时使用苏木精和伊红（HE）染色检查胎盘组织病理学。在表现出内皮功能障碍的HUVECs中，ICAM-1和VCAM-1显著上调，而HIF-1α表达显著降低。HIF-1α的过表达促进HUVECs增殖和迁移，减轻细胞凋亡和氧化应激，增强VEGF和PlGF的表达，并抑制sFlt-1、sENG和TNF-α的表达，从而促进血管生成。在RUPP模型的PE小鼠模型中，HIF-1α表达降低与ICAM-1和VCAM-1升高同时出现，导致内皮功能障碍、收缩压升高和UP/cr比值增加。相反，HIF-1α过表达改善了胎盘组织损伤和氧化应激，上调VEGF和PlGF，下调sFlt-1、sENG、TNF-α、ICAM-1和VCAM-1，并恢复血管生成能力。HIF-1α通过抑制sFlt-1/sENG/TNF-α信号通路改善PE中的内皮功能障碍，从而促进血管生成并减轻PE。
