BACKGROUND Preeclampsia is a pregnancy-specific disorder with unclear pathogenesis. Irisin, a recently identified exercise-induced factor, significantly influences lipid metabolism and cardiovascular function. Nonetheless, its role in trophoblast development during human placentation and the related intracellular signaling pathways remain poorly understood. METHODS We assessed peripheral blood irisin expression in early pregnancy among patients with preeclampsia and its correlation with key clinical indicators. In trophoblast cell lines and mice, we used exogenous irisin and viral knockdown to investigate functional changes. Phosphorylation-specific antibody arrays and dual-luciferase reporter assays were used to explore downstream molecular mechanisms, which were subsequently validated in trophoblast cell lines and relevant gene knockout mice. RESULTS In early pregnancy, patients with preeclampsia exhibit decreased peripheral blood irisin levels, occurring earlier than traditional predictive markers, such as PLGF (placental growth factor) and sFlt-1 (soluble fms-like tyrosine kinase-1). Furthermore, irisin concentration is positively correlated with proteinuria and abnormal blood pressure during pregnancy. Exogenous irisin significantly enhanced trophoblast cell migration, invasion, and proliferation while inhibiting apoptosis. It also increased STAT (signal transducers and activators of transcription) 4 phosphorylation and its binding to the GLUT (glucose transporter)-3 promoter, resulting in elevated GLUT-3 expression and glucose uptake in trophoblast cells. In vivo, increased peripheral irisin promoted embryo implantation, vascular remodeling, and enhanced glucose uptake, whereas reduced irisin resulted in a preeclampsia-like phenotype characterized by elevated blood pressure, proteinuria, renal-placental dysfunction, adipose accumulation, and restricted fetal growth. CONCLUSIONS Peripheral irisin improves preeclampsia by promoting embryo implantation and vascular remodeling through the activation of the STAT4/GLUT-3 pathway. Reduced peripheral irisin may contribute to preeclampsia-like pathologies. This study supports the advocacy for appropriate exercise during early pregnancy and provides new insights for preeclampsia prevention.

中文翻译：

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Irisin 通过促进胚胎植入和血管重塑来改善子痫前期。


背景 子痫前期是一种发病机制不明的妊娠特异性疾病。鸢尾素是最近发现的一种运动诱发因子，对脂质代谢和心血管功能有显著影响。尽管如此，它在人类胎盘过程中滋养层发育中的作用以及相关的细胞内信号通路仍然知之甚少。方法 我们评估了子痫前期患者妊娠早期外周血鸢尾素表达及其与关键临床指标的相关性。在滋养层细胞系和小鼠中，我们使用外源鸢尾素和病毒敲低来研究功能变化。磷酸化特异性抗体阵列和双荧光素酶报告基因测定用于探索下游分子机制，随后在滋养层细胞系和相关基因敲除小鼠中进行了验证。结果 在妊娠早期，子痫前期患者表现出外周血鸢尾素水平降低，比 PLGF （胎盘生长因子） 和 sFlt-1 （可溶性 fms 样酪氨酸激酶-1） 等传统预测标志物更早发生。此外，鸢尾素浓度与妊娠期间蛋白尿和血压异常呈正相关。外源性鸢尾素显著增强滋养层细胞迁移、侵袭和增殖，同时抑制细胞凋亡。它还增加了 STAT （信号转导和转录激活因子） 4 磷酸化及其与 GLUT （葡萄糖转运蛋白）-3 启动子的结合，导致滋养层细胞中 GLUT-3 表达和葡萄糖摄取升高。 在体内，外周鸢尾素增加促进胚胎着床、血管重塑和葡萄糖摄取增强，而鸢尾素减少导致子痫前期样表型，其特征是血压升高、蛋白尿、肾胎盘功能障碍、脂肪积累和胎儿生长受限。结论 外周鸢尾素通过激活 STAT4/GLUT-3 通路促进胚胎着床和血管重塑来改善子痫前期。外周鸢尾素减少可能导致子痫前期样病变。本研究支持倡导妊娠早期适当锻炼，并为预防子痫前期提供了新的见解。