Mode Switch of Ca2 + Oscillation-Mediated Uterine Peristalsis and Associated Embryo Implantation Impairments in Mouse Adenomyosis

Abstract

Adenomyosis is a debilitating gynecological disease of the uterus with no medicinal cure. The tissue injury and repair hypothesis for adenomyosis suggests that uterine hyperperistalsis or dysperistalsis plays a pivotal role in establishing adenomyotic lesions. However, specific impairments in uterine peristalsis and the underlying cellular signals for these changes in adenomyosis remain elusive. Here, we report a precision-cut uterine slice preparation that preserves in vivo uterine architecture and generates peristalsis similar to that seen in the whole uterus. We found that uterine peristalsis in neonatal mice at day 14 and adult mice at day 55 presents as bursts with multiple peaks induced by intracellular Ca2+ oscillations. Using a mouse model of adenomyosis induced by tamoxifen, a selective estrogen receptor modulator, we discovered that uterine peristalsis and Ca2+ oscillations from adenomyotic uteri on days 14 and 55 become spikes (single peaks) with smaller amplitudes. The peak frequency of Ca2+ oscillations or peristalsis does not show a difference between control and adenomyotic mice. However, both the estimated force generated by uterine peristalsis and the total Ca2+ raised by Ca2+ oscillations are smaller in uteri from adenomyotic mice. Uteri from adenomyotic mice on day 14, but not on day 55, exhibit hyperresponsiveness to oxytocin. Embryo implantations are decreased in adenomyotic adult mice. Our results reveal a mode switch from bursts to spikes (rather than an increased peak frequency) of uterine Ca2+ oscillations and peristalsis and concurrent hyperresponsiveness to oxytocin in the neonatal stage are two characteristics of adenomyosis. These characteristics may contribute to embryo implantation impairments and decreased fertility in adenomyosis.

Administration of Oxytocin Receptor Antagonist during Frozen Embryo Transfer: Potential Improvement in Live Birth Rates for Women with Recurrent Implantation Failure, Adenomyosis, and Myoma

“…Adenomyosis and myomas are also correlated with increased uterine peristalsis frequencies [14,15]. Our hypothesis posits that the administration of oxytocin receptor antagonists during ET may improve IVF outcomes in women with adenomyosis and myomas.…”

“…A study utilizing a mouse model of adenomyosis induced by tamoxifen revealed a greater frequency of uterine peristalsis and concurrent hyperresponsiveness to oxytocin in adenomyosis patients, potentially contributing to impaired embryo implantation and decreased fertility [14]. In a randomized control study involving women with endometriosis, the endometriosis group exhibited signi cantly greater serum oxytocin and PGF2α levels and uterine contractions than did the tubal factor infertility group [19].…”

Cyclic processes in the uterine tubes, endometrium, myometrium, and cervix: pathways and perturbations

“…Throughout the menstrual cycle, the myometrium exerts wave-like contractions, called uterine peristalsis, which are thought to aid in sperm transit and embryo transport ( Kunz and Leyendecker, 2002 ; Hunt et al , 2020 ; Qu et al , 2021 ). Myometrial contractions display cyclicity, increasing in strength and frequency during the proliferative phase to be maximal at ovulation and then retrograde (from the cervix to fundus), supporting sperm transit from the cervix to the uterine tube.…”

Imaging the dynamics of uterine contractions in early pregnancy

“…Uterine contractions can be measured using invasive techniques such as intrauterine pressure measurement (Künzel et al, 2014; Robuck et al, 2018) and electromyography (Bulletti and de Ziegler, 2006) or non-invasive molecular imaging techniques such as 3D ultrasounds (Bulletti and de Ziegler, 2006) or magnetic resonance imaging (Lam et al, 2018). In vivo, pressure recordings and ultrasound can themselves contribute to contractility and MRI and ultrasounds do not give spatial and quantitative waveform metrics such as amplitude, frequency, and velocity (Lovasz et al, 2013; Qu et al, 2021; Ter Haar et al, 1978). Uterine contractions have been measured by isolating either tissue strips from the uterus (Allix et al, 2008; Bafor et al, 2017; Dodds et al, 2015; Smith et al, 2007) or transverse uterine slices (Qu et al, 2021).…”

“…In vivo, pressure recordings and ultrasound can themselves contribute to contractility and MRI and ultrasounds do not give spatial and quantitative waveform metrics such as amplitude, frequency, and velocity (Lovasz et al, 2013; Qu et al, 2021; Ter Haar et al, 1978). Uterine contractions have been measured by isolating either tissue strips from the uterus (Allix et al, 2008; Bafor et al, 2017; Dodds et al, 2015; Smith et al, 2007) or transverse uterine slices (Qu et al, 2021). Tissue pieces are equilibrated in an organ bath (Talo, 1980) and spontaneous contractions or the effect of agonist induced contractions is estimated.…”