Abstract

Aberrant remodeling of uterine spiral arteries (SPA) is strongly associated with the pathogenesis of early-onset preeclampsia (EOPE). However, the complexities of SPA transformation remain inadequately understood. We conducted a single-cell RNA sequencing analysis of whole placental tissues derived from patients with EOPE and their corresponding controls, identified DAB2 as a key gene of interest and explored the mechanism underlying the communication between Extravillous trophoblast cells (EVTs) and decidual vascular smooth muscle cells (dVSMC) through cell models and a placenta-decidua coculture (PDC) model in vitro. DAB2 enhanced the motility and viability of HTR-8/SVneo cells. After exposure to conditioned medium (CM) from HTR-8/SVneo^shNC cells, hVSMCs exhibited a rounded morphology, indicative of dedifferentiation, while CM-HTR-8/SVneo^shDAB2 cells displayed a spindle-like morphology. Furthermore, the PDC model demonstrated that CM-HTR-8/SVneo^shDAB2 was less conducive to vascular remodeling. Further in-depth mechanistic investigations revealed that C-X-C motif chemokine ligand 8 (CXCL8, also known as IL8) is a pivotal regulator governing the dedifferentiation of dVSMC. DAB2 expression in EVTs is critical for orchestrating the phenotypic transition and motility of dVSMC. These processes may be intricately linked to the CXCL8/PI3K/AKT pathway, underscoring its central role in intricate SPA remodeling.

Graphical abstract

中文翻译：

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鉴定 DAB2 和 CXCL8 在早发性子痫前期子宫螺旋动脉重塑中的作用

摘要

子宫螺旋动脉（SPA）的异常重塑与早发性先兆子痫（EOPE）的发病机制密切相关。然而，人们对 SPA 转型的复杂性仍知之甚少。我们对 EOPE 患者及其相应对照的整个胎盘组织进行了单细胞 RNA 测序分析，确定 DAB2 为关键基因，并探讨了绒毛外滋养层细胞 (EVT) 与蜕膜血管平滑肌之间通讯的机制细胞（dVSMC）通过细胞模型和体外胎盘-蜕膜共培养（PDC）模型。 DAB2 增强了 HTR-8/SVneo 细胞的运动性和活力。暴露于 HTR-8/SVneo ^shNC细胞的条件培养基 (CM) 后，hVSMC 表现出圆形形态，表明去分化，而 CM-HTR-8/SVneo ^shDAB2细胞则表现出纺锤样形态。此外，PDC模型表明CM-HTR-8/SVneo ^shDAB2不太有利于血管重塑。进一步深入的机制研究表明，CXC基序趋化因子配体8（CXCL8，也称为IL8）是控制dVSMC去分化的关键调节因子。 EVT 中的 DAB2 表达对于协调 dVSMC 的表型转变和运动至关重要。这些过程可能与 CXCL8/PI3K/AKT 通路错综复杂地联系在一起，强调了其在复杂的 SPA 重塑中的核心作用。

图形概要