Bi Yanmei, Li Hao, Diao Min, Liu Qian, Huang Lu, Tao Yunkai, Wan Yantong, Lin Xuemei
Department of Anesthesiology, West China Second University Hospital, Sichuan University, No. 20, Section 3, South of Renmin Road, Chengdu, 610041, Sichuan, China.
Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, Sichuan, China.
J Transl Med. 2024 Dec 23;22(1):1140. doi: 10.1186/s12967-024-05978-y.
Preterm birth, a leading cause of perinatal mortality and morbidity, is often associated with inflammation and aberrant myometrial contractions. This study investigates the role of Piezo1, a mechanosensitive ion channel, in myometrium contraction and inflammation-associated preterm birth.
We employed Western blotting, Immunofluorescence, and Quantitative real-time PCR techniques to examine Piezo1 expression in uterine tissues. Functional assays, including myometrial contractility studies and cell contraction assays, were conducted to elucidate the effects of Piezo1 on myometrial contractions. Piezo1 inhibitors and gene knockdown techniques were used to investigate the impact of Piezo1 on inflammation-associated preterm birth, complemented by inflammatory cytokine profiling and calcium imaging to investigate the mechanism.
Our findings reveal that Piezo1 is the predominant mechanosensitive channel in mouse myometrium tissue and mouse primary uterine smooth muscle (pUSMCs), with increased expression during mouse and human pregnancy. Following lipopolysaccharide (LPS) intrauterine injection, Piezo1 mRNA and protein levels were elevated in the mouse uterine smooth muscle layer. Direct pharmacologic activation of Piezo1 by Yoda1 increased the contraction of pUSMCs and shortened the pregnancy duration. In contrast, inhibition with Gsmtx4 or siRNA knockdown of Piezo1 attenuated LPS-induced pUSMCs contraction and spontaneous uterine myometrium contraction. Additionally, blocking or knocking down Piezo1 prolonged the pregnancy in an LPS-induced preterm birth model. Yoda1 stimulation increased intracellular Ca levels in pUSMCs, while Gsmtx4 reduced these levels. Gsmtx4 decreased cox-2 expression and inflammation factors in LPS-stimulated pUSMCs.
These results suggest that Piezo1 acts as a critical regulator of uterine function, and its overexpression may predispose to preterm labor through heightened myometrial activity and inflammation. The study underscores the potential of targeting Piezo1 as a therapeutic strategy to mitigate preterm birth associated with uterine inflammation.
早产是围产期发病和死亡的主要原因，通常与炎症和子宫肌层异常收缩有关。本研究调查机械敏感离子通道Piezo1在子宫肌层收缩及炎症相关早产中的作用。
我们采用蛋白质免疫印迹法、免疫荧光法和定量实时聚合酶链反应技术检测Piezo1在子宫组织中的表达。进行了包括子宫肌层收缩性研究和细胞收缩试验在内的功能试验，以阐明Piezo1对子宫肌层收缩的影响。使用Piezo1抑制剂和基因敲低技术研究Piezo1对炎症相关早产的影响，并辅以炎性细胞因子分析和钙成像来研究其机制。
我们的研究结果表明，Piezo1是小鼠子宫肌层组织和小鼠原代子宫平滑肌（pUSMCs）中主要的机械敏感通道，在小鼠和人类妊娠期间表达增加。宫内注射脂多糖（LPS）后，小鼠子宫平滑肌层中Piezo1的mRNA和蛋白水平升高。Yoda1对Piezo1的直接药理学激活增加了pUSMCs的收缩并缩短了妊娠期。相比之下，用Gsmtx4抑制或通过小干扰RNA敲低Piezo1可减弱LPS诱导的pUSMCs收缩和子宫肌层自发性收缩。此外，在LPS诱导的早产模型中，阻断或敲低Piezo1可延长妊娠期。Yoda1刺激增加了pUSMCs中的细胞内钙水平，而Gsmtx4降低了这些水平。Gsmtx4降低了LPS刺激的pUSMCs中环氧合酶-2（cox-2）的表达和炎症因子水平。
这些结果表明，Piezo1是子宫功能的关键调节因子，其过表达可能通过增强子宫肌层活性和炎症导致早产。该研究强调了将Piezo1作为一种治疗策略来减轻与子宫炎症相关的早产的潜力。
