A protein called Piezo1 has been linked to preterm labor, according to new research published in The Journal of Physiology. The work was carried out by researchers at the University of Nevada. Piezo1, they found, is responsible for regulating the mechanics of the uterus by keeping it relaxed to ensure it continues to stretch and expand during the 40 weeks of a full term pregnancy.
“It is troubling that there are still no drugs available to stop preterm labor,” said lead author, Iain Buxton of the Myometrial Research Group at the University of Nevada. “Thanks to the Nobel Prize winning discovery of Piezo proteins, which are responsible for how the body responds to mechanical force, and our investigation we are now closer to developing a treatment.”
The World Health Organization (WHO) estimates that each year approximately 15 million babies are born preterm (i.e. prior to 37 weeks gestation). While there has been some progress in finding genes and other potential causes, there is still a lot of work ahead. The identification of Piezo1’s role to maintain stretch-activation channels in pregnancy opens the door for drugs and therapies to be developed that could one day treat or delay this condition.
The muscular outer layer of the uterus is peculiar because it is the only muscle that it is not regulated by nerves and it must remain dormant for 40 weeks, despite significant expansion and stretch, as the fetus develops into a baby. The researchers from University of Nevada studied tissue samples of the smooth muscle of the uterus to explore the mechanistic pathways to better understand the dynamics controlling the uterus and what maintains a state of relaxation of the muscle until labor.
According to this recent work, stretching the uterus tissue activates Piezo1 channels. This drives the flow of calcium molecules generating a signaling cascade that activates the enzyme nitric oxide synthase to produce the molecule nitric oxide. This Piezo1 cascade promotes and maintains the dormant state of the uterus.
Piezo1 works in a dose-dependent manner. It is upregulated by the chemical Yoda1 and downregulated by a chemical called Dooku1. When Piezo1 is upregulated, the uterus remains in a relaxed state. However, in preterm tissue, the expression of Piezo1 is significantly downregulated, so the uterus contracts and initiates labor.
Buxton said, “Pregnancy is the most impressive example of a human muscle enduring mechanical stress for a prolonged period. Finding Piezo1 in the muscular layer of the uterus means the uterus is controlled locally and is coordinated by a stretch-activated mechanism rather than hormonal influence from the ovaries or the placenta, which has been the assumption.”
He added that, “Piezo1 and its relaxation mechanism provide a target for us which we could potentially activate with drugs. We need to test this with further studies and we hope to carry out clinical trials in the future.”
Contraction and relaxation were assessed in tissue samples compared for the following gestational periods: non-pregnant, term non-laboring, term laboring, preterm non-laboring and preterm laboring. The presence of Piezo1 channels was discovered using molecular tools while pregnant tissues contracting in a muscle bath were stimulated with Piezo1 channel activator and inhibitor to characterize the regulation of quiescence.
The researchers say that more work is needed to improve understanding of how all the molecular signals and steps involved in the Piezo1 channel regulate the relaxation of the uterus and whether more chemicals are working together with this protein.
