Piezo1 overexpression in the uterus contributes to myometrium contraction and inflammation-associated preterm birth

Background:
Preterm birth, a leading cause of perinatal mortality and morbidity, is commonly associated with inflammation and abnormal myometrial contractions. This study aims to explore the role of Piezo1, a mechanosensitive ion channel, in regulating myometrial contractions and inflammation-related preterm birth.
Methods:
Piezo1 expression in uterine tissues was assessed using Western blotting, immunofluorescence, and quantitative real-time PCR. To examine the effects of Piezo1 on myometrial contractility, functional assays including myometrial contraction studies and cell-based contraction assays were performed. The impact of Piezo1 on inflammation-associated preterm birth was investigated using Piezo1 inhibitors and gene knockdown strategies. Inflammatory cytokine profiling and calcium imaging were employed to further explore the underlying mechanisms.
Results:
Piezo1 was identified as the primary mechanosensitive channel in both mouse myometrial tissue and primary uterine smooth muscle cells (pUSMCs), with its expression significantly increasing during pregnancy in both mice and humans. After intrauterine lipopolysaccharide (LPS) injection, Piezo1 mRNA and protein levels were elevated in the uterine smooth muscle layer of mice. Pharmacological activation of Piezo1 with Yoda1 enhanced the contraction of pUSMCs and reduced pregnancy duration. Conversely, inhibition of Piezo1 with Gsmtx4 or siRNA-mediated knockdown attenuated LPS-induced pUSMC contraction and spontaneous myometrial contractions. Moreover, blocking or knocking down Piezo1 prolonged pregnancy in an LPS-induced preterm birth model. Yoda1 stimulation led to increased intracellular calcium levels in pUSMCs, while Gsmtx4 reduced these levels. Gsmtx4 also decreased the expression of cyclooxygenase-2 (COX-2) and other inflammatory markers in LPS-stimulated pUSMCs.
Conclusions:
These findings suggest that Piezo1 is a crucial regulator of uterine function, with overexpression potentially contributing to preterm labor through increased myometrial activity and inflammation. The results highlight the therapeutic potential of targeting Piezo1 to modulate uterine contractions and inflammation in the context of preterm birth.