PIEZO channels link mechanical forces to uterine contractions in parturition
Yunxiao ZhangiD, Sejal A KiniiD, Sassan A MishkanianiD, Renhao LuoiD, Saba Heydari SeradjiD, Verina H. LeungiD, Yu WangiD, M. Rocio Servin‐VencesiD, William Thomas KeenaniD, Utku Sonmez, Oleg Yarishkin, Manuel Sánchez-AlaveziD, Yuejia LiuiD, Xin JiniD, Darren J. LipomiiD, Ye LiiD, Michael PetrascheckiD, Antonina I. FrolovaiD, Sarah K. EnglandiD, Ardem PatapoutianiD
Abstract
AbstractMechanical forces are extensively involved in pregnancy and parturition, but their precise roles and mechanisms remain poorly understood. Here, we identify mechanically activated ion channels PIEZO1 and PIEZO2 as key mechanotransducers required for labor progression. Genetic deletion of Piezo1 and Piezo2 in mice resulted in weakened uterine contractions and severe parturition defects. Tissue-specific knockouts revealed that deletion in either the uterus or sensory neurons alone caused modest defects, whereas combined loss significantly impaired labor, demonstrating additive effects. Single-nuclei sequencing showed that loss of PIEZO reduced expression of connexin43 (Gja1), a gap junction protein in uterine smooth muscle cells, suggesting a mechanistic link to impaired contraction. These findings highlight the critical role of PIEZO channels in mechanotransduction during parturition and suggest therapeutic targets for labor dysfunction.
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Claude Sonnet 4.6 · xhigh effort · 8 Nov 2026 · from the full text of version 1 (18 Sept 2025) · CC BY 4.0
Deleting Piezo1 and Piezo2 together in mice weakens uterine contractions and prolongs labor; uterine and sensory-neuron deletions act additively, and knockout uteri show reduced Gja1 (connexin43).
The paper states that mechanical forces are involved in pregnancy and parturition but their roles and mechanisms are poorly understood. It notes that most candidate pathways also respond to biochemical cues, whereas PIEZO1 and PIEZO2 are directly force-gated and have no known endogenous chemical ligands, so their loss points to mechanosensation.
Key results
ShownCombined Piezo1/2 deletion (HoxB8-Cre) in female mice causes prolonged labor and incomplete delivery by gestational day 20 (GD20). Single knockouts show no evident parturition deficit, and gestation looks normal.
Retained embryos were present in many double knockouts at GD20, while all animals started parturition on GD19. Embryo number and embryo size were similar to controls. Cervix trichrome and uterine H&E histology showed no discernible abnormalities. · Piezo1 and Piezo2 knockout mice impair…
ShownIntrauterine pressure telemetry in freely moving dams shows weaker contractions and delayed labor onset in double knockouts. Most knockouts later showed a compensatory rise in contraction strength.
Data from 9 animals per group. Average contraction-peak pressure in the 2 h after the first pup was significantly lower in knockouts (t-test), and the interval between pups was longer. About half of knockouts delivered the first pup after ZT3, while all controls delivered before ZT3. · Loss of Piezo1 and Piezo2 impairs uterine…; Figure legends
ShownPiezo1/2 loss in the uterus (PGR-Cre) and in caudal sensory neurons (intrathecal AAV-Cre) contribute additively to labor defects. Combined deletion gives the strongest phenotype, milder than the HoxB8-Cre knockout.
A generalized least squares model estimated effects on contraction intensity of -16.07 mmHg (uterus) and -47.11 mmHg (DRG). Two combined-knockout animals did not finish labor by GD20, and the pup interval was significantly longer only in combined knockouts. · Piezo1/2 in the uterus and sensory nerves…
SuggestedsnRNA-seq of GD18.5 uterus found few differentially expressed genes between knockout and control. Most were in smooth muscle cells, and Gja1 (connexin43) was reduced, a possible link to impaired contraction.
HoxB8-Cre Piezo1/2 knockout vs control uteri. Cell-type proportions were similar between genotypes. Lower Gja1 in smooth muscle was confirmed by smFISH, with controls showing higher late-gestation Gja1 than knockouts. · PIEZOs are required for upregulation of gap…
ShownIn mouse, Piezo1 is broadly expressed in uterine cells while Piezo2 is sparse in the uterus. Piezo2 sensory fibers mainly innervate the lower reproductive tract. Human term myometrium shows the same pattern.
smFISH at GD18.5 in mouse and in human non-labor term myometrium (3 donors). Light-sheet and confocal imaging of Piezo2-labeled fibers. Retrograde CTB labeling gave no overlap with Sst among 240 labeled neurons from 4 animals. · Distinct expression patterns of Piezo1 and…; Figure legends
Methods, data and reproducibility
Conditional Piezo1/2 knockout mice (HoxB8-Cre; PGR-Cre plus intrathecal AAV-Cre) were compared with controls using implanted intrauterine pressure telemetry, video-scored delivery, smFISH and snRNA-seq of GD18.5 uterus. Expression was also mapped in mouse and human reproductive tissue.
- Intrauterine pressure telemetry and delivery timing in HoxB8-Cre Piezo1/2 double knockouts vs controls · mouse · n = 9 animals in each group
- snRNA-seq of GD18.5 uterine horns, knockout vs control · mouse · SCP2924
- smFISH of PIEZO1/PIEZO2 in term, non-labor human myometrium · human · n = 3 donor specimens
- Retrograde CTB labeling of uterus/cervix-innervating DRG neurons, overlap with Sst · mouse · n = 240 neurons from 4 animals
- Published single-cell data (mouse estrous cycle; laboring human term myometrium) used for expression patterns · mouse and human
- Methods & tools
- RNAscope smFISH, CellProfiler, DSI HD-X11 telemetry, PIPseq T2 v4.0PLUS 3' kit, PIPseeker, CellBender, Seurat, DoubletFinder, Harmony, Propeller, SVA-EdgeR, GraphPad Prism
- Reagents & environment
- Ponemah 5.20 used for telemetry export; Fluoview v2.4.1.198 for confocal acquisition. Analysis software versions are not given.
- Reproducibility gaps
- Analysis code is stated to be deposited on GitHub in future, with no URL given. The snRNA-seq data are at the Broad Institute Single Cell Portal under SCP2924, but no URL is printed.
Limitations (6)
- AAV-mediated DRG knockouts were less efficient and more variable than HoxB8-Cre knockouts, and Piezo2 in caudal DRG stayed higher. This is consistent with their milder phenotype; HoxB8-Cre may also target other cell types. · stated by the authors
- The models did not target all cell types (for example vascular and lymphatic endothelium), and loss of Piezo1/2 did not remove uterine hypertrophy or cervical remodeling, so other mechanosensitive pathways likely contribute. · stated by the authors
- Direct validation in humans is difficult because PIEZO loss-of-function has severe consequences; functional evidence is from mice only. · stated by the authors
- Animals with proprioceptive defects can be recognized by the observer, so data collection was not truly blinded for those groups. · stated by the authors
- The Gja1 link is correlative: Gja1 is reduced in knockouts, but no Gja1 manipulation or rescue is shown. Calcium signaling is proposed, not measured. · noted in this summary
- AAV-Cre sensory-neuron knockout caused proprioceptive defects from about GD14.5, which could confound labor behavior and is not separated from effects on a sensory reflex. · noted in this summary
Who should read:Read this if you study mechanosensation, uterine physiology or labor dysfunction and want in vivo genetic evidence plus an snRNA-seq dataset of PIEZO-deficient mouse uterus.
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