Ingles Judith A, Rodriguez Zahidee, Fornes Daiana, Ying Lihua, Han Xiaoyuan, Cornfield David N, Alvira Cristina M
Center for Excellence in Pulmonary Biology, Department of Pediatrics, Stanford University School of Medicine, California, USA.
Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, California, USA.
FASEB J. 2025 Feb 28;39(4):e70418. doi: 10.1096/fj.202402949R.
Inflammation is a key initiating event in both spontaneous term and preterm labor. However, the link between inflammation and the onset of labor remains incompletely understood. We identified the transient receptor potential vanilloid 4 (TRPV4) channel as a critical regulator of myometrial calcium (Ca) entry and contractility. In this study, we aimed to determine if the TRPV4 channel regulates uterine inflammation and its subsequent effects on myometrial contractility in experimental preterm labor. We demonstrated that global loss of TRPV4 protected mice against inflammation-induced preterm labor, decreased baseline myometrial contractility, and diminished lipopolysaccharide-stimulated increases in oxytocin-mediated contraction. Pharmacological inhibition of TRPV4 in human myometrial smooth muscle cells (SMC) blunted lipopolysaccharide (LPS)-induced activation of nuclear factor kappa-B (NFκB) and pro-inflammatory cytokine expression. In contrast, pharmacologic activation of TRPV4 augmented LPS-induced NFκB activation. Further, TRPV4-mediated NFκB activation was dependent on extracellular Ca entry in myometrial SMC. Together, these data show that extracellular Ca entry via TRPV4 potentiates NFκB-mediated inflammation and increases susceptibility to preterm labor. The ability of TRPV4 to modulate both myometrial inflammation and contractility, processes central to the onset of preterm and term labor, suggests that the TRPV4 channel may represent a novel therapeutic target for the treatment of premature birth.
炎症是足月自然分娩和早产的关键起始事件。然而，炎症与分娩发动之间的联系仍未完全明确。我们发现瞬时受体电位香草酸受体4（TRPV4）通道是子宫肌层钙内流和收缩性的关键调节因子。在本研究中，我们旨在确定TRPV4通道是否调节实验性早产中的子宫炎症及其对子宫肌层收缩性的后续影响。我们证明，TRPV4的整体缺失可保护小鼠免受炎症诱导的早产，降低子宫肌层基线收缩性，并减少脂多糖刺激引起的催产素介导的收缩增加。在人子宫肌层平滑肌细胞（SMC）中对TRPV4进行药理抑制可减弱脂多糖（LPS）诱导的核因子κB（NFκB）激活和促炎细胞因子表达。相反，TRPV4的药理激活增强了LPS诱导的NFκB激活。此外，TRPV4介导的NFκB激活依赖于子宫肌层SMC中的细胞外钙内流。总之，这些数据表明，通过TRPV4的细胞外钙内流增强了NFκB介导的炎症，并增加了早产易感性。TRPV4调节子宫肌层炎症和收缩性的能力，这是早产和足月分娩发动的核心过程，表明TRPV4通道可能是治疗早产的新治疗靶点。
