Qu Mingzi, Lu Ping, Bellve Karl, Lifshitz Lawrence M, ZhuGe Ronghua
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, United States.
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, United States.
Front Physiol. 2021 Nov 4;12:744745. doi: 10.3389/fphys.2021.744745. eCollection 2021.
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 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 Ca oscillations. Using a mouse model of adenomyosis induced by tamoxifen, a selective estrogen receptor modulator, we discovered that uterine peristalsis and Ca oscillations from adenomyotic uteri on days 14 and 55 become spikes (single peaks) with smaller amplitudes. The peak frequency of Ca 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 Ca raised by Ca 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 Ca 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.
子宫腺肌病是一种无法通过药物治愈的、使人虚弱的妇科疾病。子宫腺肌病的组织损伤与修复假说认为，子宫的过度蠕动或蠕动异常在子宫腺肌病病变的形成中起关键作用。然而，子宫蠕动的具体损伤以及子宫腺肌病中这些变化的潜在细胞信号仍然不清楚。在此，我们报告了一种精密切割的子宫切片制备方法，该方法保留了子宫结构，并产生与整个子宫相似的蠕动。我们发现，出生后第14天的新生小鼠和第55天的成年小鼠的子宫蠕动表现为细胞内钙振荡诱导的具有多个峰值的爆发。使用他莫昔芬（一种选择性雌激素受体调节剂）诱导的子宫腺肌病小鼠模型，我们发现出生后第14天和第55天的子宫腺肌病子宫的蠕动和钙振荡变成了振幅较小的尖峰（单峰）。钙振荡或蠕动的峰值频率在对照小鼠和子宫腺肌病小鼠之间没有差异。然而，子宫腺肌病小鼠子宫的蠕动产生的估计力和钙振荡升高的总钙量均较小。出生后第14天而非第55天的子宫腺肌病小鼠的子宫对催产素表现出高反应性。成年子宫腺肌病小鼠的胚胎着床减少。我们的结果揭示了子宫钙振荡和蠕动从爆发到尖峰的模式转变（而非峰值频率增加），并且在新生阶段对催产素的同时高反应性是子宫腺肌病的两个特征。这些特征可能导致子宫腺肌病中的胚胎着床受损和生育力下降。
