Novel identification and modulation of the mechanosensitive Piezo1 channel in human myometrium

Abstract

Approximately 10% of US births deliver preterm before 37 weeks of completed gestation. Premature infants are at risk for life‐long debilitating morbidities and death, and spontaneous preterm labour explains 50% of preterm births. In all cases existing treatments are ineffective, and none are FDA approved. The mechanisms that initiate preterm labour are not well understood but may result from dysfunctional regulation of quiescence mechanisms. Human pregnancy is accompanied by large increases in blood flow, and the uterus must enlarge by orders of magnitude to accommodate the growing fetus. This mechanical strain suggests that stretch‐activated channels may constitute a mechanism to explain gestational quiescence. Here we identify for the first time that Piezo1, a mechanosensitive cation channel, is present in the uterine smooth muscle and microvascular endothelium of pregnant myometrium. Piezo is downregulated during preterm labour, and stimulation of myometrial Piezo1 in an organ bath with the agonist Yoda1 relaxes the tissue in a dose‐dependent fashion. Further, stimulation of Piezo1 while inhibiting protein kinase A, AKT, or endothelial nitric oxide synthase mutes the negative inotropic effects of Piezo1 activation, intimating that actions on the myocyte and endothelial nitric oxide signalling contribute to Piezo1‐mediated contractile dynamics. Taken together, these data highlight the importance of stretch‐activated channels in pregnancy maintenance and parturition, and identify Piezo1 as a tocolytic target of interest. Key points Spontaneous preterm labour is a serious obstetric dilemma without a known cause or effective treatments. Piezo1 is a stretch‐activated channel important to muscle contractile dynamics. Piezo1 is present in the myometrium and is dysregulated in women who experience preterm labour. Activation of Piezo1 by the agonist Yoda1 relaxes the myometrium in a dose‐dependent fashion, indicating that Piezo1 modulation may have therapeutic benefits to treat preterm labour.

β3 adrenergic receptor activation modulates connexin 43 activity to relax human myometrium

“…All pregnant human myometrial tissue collection adhered to the regulations set by the Declaration of Helsinki and approved by the Institutional Review Board at the University of Nevada Biomedical Review Committee for the protection of human subjects. Women with a singleton pregnancy that were having a Cesarean section (C/S) gave their verbal and written consent to have a piece of uterine smooth muscle tissue excised as described [ 14 , 31 ]. We collect all de-identified data on the treatments and pregnancy course prior to C/S as well as the presence and degree, or absence of infection, mother’s BMI, sex of the infant, smoking status of the mother and social indicators including socioeconomic status, prenatal care, and maternal education when available.…”

Ion channels and transporters keep ideas flowing

“…In our Special Issue, Barnett et al. (2023) share their discovery that Piezo1 has key functions in a very different tissue, namely human myometrium. There, it is modulated by protein kinase A/AKT/endothelial nitric oxide synthase‐mediated paracrine signalling between the microvascular endothelium and uterine smooth muscle, thereby ensuring quiescence during gestation.…”

“…It is noteworthy that less Piezo1 is expressed in myometrium from women experiencing preterm labour. These studies therefore reveal potential targets for the development of therapies to mitigate this condition and its extenuating consequences (Barnett et al., 2023). To complement these insights, an accompanying Journal Club article (Majhi et al., 2023) concisely and thoroughly considers the implications of the study by Barnett et al.…”

“…To complement these insights, an accompanying Journal Club article (Majhi et al., 2023) concisely and thoroughly considers the implications of the study by Barnett et al. (2023).…”

Piezo1 activation by stretching of uterine myometrium supports pregnancy and prevents preterm labour

“…The mechanosensitive channels present in the myometrium likely sense this mechanical stretch and their activation triggers a mechanism that sustains quiescence. In a recent study published in The Journal of Physiology, Barnett et al set out to characterize the expression pattern and (patho)physiological role of the mechanosensitive channel PIEZO1 in quiescence and PTL mechanisms of the human myometrium (Barnett et al, 2022). They found that PIEZO1 levels are comparable in the myometrium of non-pregnant women and women at term or preterm but without initiation of labour.…”