Yo Jennifer H, Palmer Kirsten R, Nikolic-Paterson David, Kerr Peter G, Marshall Sarah A
Department of Nephrology, Monash Health, Clayton, VIC, Australia; The Ritchie Centre, Department of Obstetrics and Gynaecology, School of Clinical Sciences, Monash University, Clayton, VIC, Australia; Department of Medicine, School of Clinical Health Sciences, Monash University, Clayton, VIC, Australia.
The Ritchie Centre, Department of Obstetrics and Gynaecology, School of Clinical Sciences, Monash University, Clayton, VIC, Australia; Monash Women's, Monash Health, Clayton, VIC, Australia.
Placenta. 2025 Jan;159:146-153. doi: 10.1016/j.placenta.2024.12.010. Epub 2024 Dec 21.
Tacrolimus is a cornerstone of immunosuppression in solid organ transplants, but its use is linked with the development of endothelial dysfunction. Pregnant solid organ transplant recipients are four to six times more likely to develop preeclampsia, which is also associated with endothelial dysfunction. Therefore, this in vitro study investigated the acute effects of tacrolimus on the expression of common angiogenic factors related to preeclampsia, and effects on angiogeneis in primary human tissues.
Primary human umbilical vein endothelial cells (HUVECs) were exposed to tacrolimus (0, 5, 20, 50 ng/mL) for 24h alone, or in combination with tumour necrosis factor (TNF, 10 ng/mL) and high dose glucose (25 mM). Cell culture concentrations of sFlt-1, PlGF and activin A were measured. In addition, the effect of tacrolimus on markers of endothelial dysfunction and permeability were assessed, as were the effect of tacrolimus on tube formation. Angiogenic factors and mRNA markers of oxidative stress and inflammation were also assessed in primary placental tissue after an acute 24 h exposure to tacrolimus.
Tacrolimus exposure significantly reduced HUVEC secretion of PlGF, increased production of activin A, andreduced tubular structure formation without impacting cell permeability or viability. There was no change in ICAM1 or VCAM1 expression in HUVECs treated with tacrolimus treatment alone, however co-culture with TNF significantly increased expression of ICAM1 and VCAM1. In placental explants tacrolimus did not change angiogenic factor production or markers of inflammation or oxidative stress.
An acute tacrolimus exposure reduced PlGF secretion and impaired angiogenesis in primary endothelial cells, without affecting. These findings provide a potential mechanistic basis for tacrolimus to contribute to the endothelial dysfunction contributing to preeclampsia.
他克莫司是实体器官移植免疫抑制的基石，但其使用与内皮功能障碍的发生有关。怀孕的实体器官移植受者发生先兆子痫的可能性高出四至六倍，而先兆子痫也与内皮功能障碍有关。因此，本体外研究调查了他克莫司对与先兆子痫相关的常见血管生成因子表达的急性影响，以及对原代人体组织血管生成的影响。
将原代人脐静脉内皮细胞（HUVECs）单独暴露于他克莫司（0、5、20、50 ng/mL）24小时，或与肿瘤坏死因子（TNF，10 ng/mL）和高剂量葡萄糖（25 mM）联合暴露。测量细胞培养物中sFlt-1、PlGF和激活素A的浓度。此外，评估了他克莫司对内皮功能障碍和通透性标志物的影响，以及他克莫司对管形成的影响。在急性暴露于他克莫司24小时后，还评估了原代胎盘组织中的血管生成因子以及氧化应激和炎症的mRNA标志物。
暴露于他克莫司显著降低了HUVECs中PlGF的分泌，增加了激活素A的产生，并减少了管状结构的形成，而不影响细胞通透性或活力。单独用他克莫司处理的HUVECs中ICAM1或VCAM1的表达没有变化，然而与TNF共培养显著增加了ICAM1和VCAM1的表达。在胎盘外植体中，他克莫司没有改变血管生成因子的产生或炎症或氧化应激的标志物。
急性暴露于他克莫司会降低原代内皮细胞中PlGF的分泌并损害血管生成，而不会产生影响。这些发现为他克莫司导致先兆子痫的内皮功能障碍提供了潜在的机制基础。
