Scientists discover how the uterus knows when to push during childbirth

Successful childbirth depends on the uterus producing steady, well-organized contractions that move the baby safely through delivery. Hormones such as progesterone and oxytocin play a major role in controlling this process. For years, however, researchers have also suspected that physical forces involved in pregnancy and birth, including stretching and pressure, contribute in important ways.

New research from Scripps Research, published in Science, now shows how the uterus detects and responds to these physical forces at the molecular level. The findings shed light on why labor sometimes slows or begins too early and could guide future efforts to improve treatments for pregnancy and delivery complications.

"As the fetus grows, the uterus expands dramatically, and those physical forces reach their peak during delivery," says senior author Ardem Patapoutian, a Howard Hughes Medical Institute Investigator and the Presidential Endowed Chair in Neurobiology at Scripps Research. "Our study shows that the body relies on special pressure sensors to interpret these cues and translate them into coordinated muscle activity."

Patapoutian shared the 2021 Nobel Prize in Physiology or Medicine for identifying the cellular sensors that allow organisms to detect touch and pressure. These sensors are ion channels built from proteins known as PIEZO1 and PIEZO2, which enable cells to respond to mechanical force.

In the new study, researchers found that PIEZO1 and PIEZO2 perform separate but complementary tasks during labor. PIEZO1 operates primarily within the smooth muscle of the uterus, where it detects rising pressure as contractions strengthen. PIEZO2, in contrast, is located in sensory nerves in the cervix and vagina. It becomes activated as the baby stretches these tissues, triggering a neural reflex that boosts uterine contractions.

Together, these sensors convert stretch and pressure into electrical and chemical signals that help synchronize contractions. If one pathway is disrupted, the other can partially compensate, helping labor continue.

To test how essential these sensors are, the team used mouse models in which PIEZO1 and PIEZO2 were selectively removed from either uterine muscle or surrounding sensory nerves. Tiny pressure sensors measured contraction strength and timing during natural labor.

Mice lacking both PIEZO proteins showed weaker uterine pressure and delayed births, indicating that muscle-based sensing and nerve-based sensing normally work together. When both systems were lost, labor was significantly impaired.

Further investigation revealed that PIEZO activity helps regulate levels of connexin 43, a protein that forms gap junctions. These microscopic channels connect neighboring smooth muscle cells so they contract together rather than independently. When PIEZO signaling was reduced, connexin 43 levels dropped and contractions became less coordinated.

"Connexin 43 is the wiring that allows all the muscle cells to act together," says first author Yunxiao Zhang, a postdoctoral research associate in Patapoutian's lab. "When that connection weakens, contractions lose strength."

Samples of human uterine tissue showed patterns of PIEZO1 and PIEZO2 expression similar to those seen in mice. This suggests that a comparable force-sensing system likely operates in people. The findings may help explain labor problems marked by weak or irregular contractions that prolong delivery.

The results also align with clinical observations that fully blocking sensory nerves can lengthen labor.

"In clinical practice, epidurals are given in carefully controlled doses because blocking sensory nerves completely can make labor much longer," notes Zhang. "Our data mirror that phenomenon; when we removed the sensory PIEZO2 pathway, contractions weakened, suggesting that some nerve feedback promotes labor."

The study opens the door to more targeted approaches to managing labor and pain. If researchers can develop safe ways to adjust PIEZO activity, it may become possible to either slow or strengthen contractions when needed. For those at risk of preterm labor, a PIEZO1 blocker, if developed, could work alongside current medications that relax uterine muscle by limiting calcium entry into cells. On the other hand, activating PIEZO channels might help restore contractions in stalled labor.

Although these applications remain far off, the underlying biology is becoming clearer.

The research team is now examining how mechanical sensing interacts with hormonal control during pregnancy. Earlier studies show that progesterone, the hormone that keeps the uterus relaxed, can suppress connexin 43 expression even when PIEZO channels are active. This helps prevent contractions from starting too soon. As progesterone levels fall near the end of pregnancy, PIEZO-driven calcium signals may help set labor in motion.

"PIEZO channels and hormonal cues are two sides of the same system," points out Zhang. "Hormones set the stage, and force sensors help determine when and how strongly the uterus contracts."

Future studies will focus on the sensory nerve networks involved in childbirth, since not all nerves around the uterus contain PIEZO2. Some may respond to different signals and act as backup systems. Distinguishing nerves that promote contractions from those that transmit pain could eventually lead to more precise pain relief methods that do not slow labor.

For now, the findings highlight that the body's ability to sense physical force extends beyond touch and balance. It also plays a central role in one of biology's most critical processes.

"Childbirth is a process where coordination and timing are everything," says Patapoutian. "We're now starting to understand how the uterus acts as both a muscle and a metronome to ensure that labor follows the body's own rhythm."

In addition to Patapoutian and Zhang, authors of the study "PIEZO channels link mechanical forces to uterine contractions in parturition," include Sejal A. Kini, Sassan A. Mishkanian, Oleg Yarishkin, Renhao Luo, Saba Heydari Seradj, Verina H. Leung, Yu Wang, M. Rocío Servín-Vences, William T. Keenan, Utku Sonmez, Manuel Sanchez-Alavez, Yuejia Liu, Xin Jin, Li Ye and Michael Petrascheck of Scripps Research; Darren J. Lipomi of the University of California San Diego; and Antonina I. Frolova and Sarah K. England of WashU Medicine.

This work was supported by the Abide-Vividion Foundations; the Baxter Foundation; the BRAIN Initiative; the Chan Zuckerberg Initiative; the Dana Foundation; the Dorris Scholar Award; the George E. Hewitt Foundation for Medical Research postdoctoral fellowship; the Howard Hughes Medical Institute Investigators; the Merck Fellow of the Damon Runyon Cancer Research Foundation (DRG-2405-20); the National Institutes of Health (NIH Director's New Innovator Award DP2DK128800, and grants R35 NS105067, R01 AT012051 and R01 AG067331); the National Science Foundation (grant CMMI-2135428); the WashU Reproductive Specimen Processing and Banking Biorepository (ReProBank); and the Whitehall Foundation.