Division of Maternal-Fetal Medicine & Perinatal Research, Department of Obstetrics & Gynecology, The University of Texas Medical Branch at Galveston, Galveston, TX, USA.
Biol Reprod. 2021 Feb 11;104(2):445-456. doi: 10.1093/biolre/ioaa192.
Pro-pregnancy hormone progesterone (P4) helps to maintain a quiescent status of uterine tissues during gestation. However, P4's functional role in maintaining fetal membrane (amniochorion) integrity remains unclear. P4 functions through its membrane receptors (progesterone receptor membrane components (PGRMCs)) as fetal membrane cells lack nuclear receptors. This study screened the differential expression of PGRMCs in the fetal membranes and tested P4-PGRMC interactions under normal and oxidative stress (OS) conditions expected that can disrupt P4-PGRMC interactions impacting fetal membrane stability resulting in parturition. Human fetal membranes were collected from term and preterm deliveries (N = 5). Immunohistochemistry and western blot localized and determined differential expression of P4 receptors. Primary amnion epithelial, mesenchymal (AMCs), and chorion cell were treated with P4 alone or co-treated (P4 + OS induced by cigarette smoke extract (CSE)). Proximity ligation assay (PLA) documented P4-receptor binding, whereas P4 enzyme-linked immunosorbent assay documented culture supernatant levels. Immunohistology confirmed lack of nuclear progesterone receptors; however, confirmed expressions of PGRMC 1 and 2. Term labor (P = 0.01) and preterm rupture (P = 0.01) are associated with significant downregulation of PGRMC2. OS-induced differential downregulation of PGRMCs in both amnion and chorion cells (all P < 0.05) and downregulates P4 release (AMCs; P = 0.01). The PLA showed preferential receptor-ligand binding in amnion and chorion cells. Co-treatment of P4 + CSE did not reverse CSE-induced effects. In conclusion, P4-PGRMCs interaction maintains fetal membranes' functional integrity throughout pregnancy. Increased OS reduces endogenous P4 production and cell type-dependent downregulation of PGRMCs. These changes can lead to fetal membrane-specific "functional progesterone withdrawal," contributing to the dysfunctional fetal membrane status seen at term and preterm conditions.
孕激素(progesterone, P4)作为一种妊娠激素，有助于妊娠期间维持子宫组织的静止状态。然而，P4 在维持胎膜完整性方面的功能作用尚不清楚。P4 通过其膜受体（孕激素受体膜成分（PGRMCs））发挥作用，因为胎膜细胞缺乏核受体。本研究筛选了 PGRMCs 在胎膜中的差异表达，并在正常和氧化应激（OS）条件下测试了 P4-PGRMC 相互作用，预计 OS 条件下会破坏 P4-PGRMC 相互作用，影响胎膜稳定性，导致分娩。从足月和早产分娩中收集了人胎膜（N=5）。免疫组织化学和 Western blot 定位和确定了 P4 受体的差异表达。单独用 P4 或共同用 P4 处理（用香烟烟雾提取物（CSE）诱导的 P4+OS）处理原代羊膜上皮细胞、间质（AMCs）和绒毛膜细胞。邻近连接分析（PLA）记录了 P4-受体结合，而 P4 酶联免疫吸附测定记录了培养上清液水平。免疫组织化学证实缺乏核孕激素受体；然而，证实了 PGRMC1 和 2 的表达。足月分娩（P=0.01）和早产破裂（P=0.01）与 PGRMC2 的显著下调相关。OS 诱导的羊膜和绒毛膜细胞中 PGRMCs 的差异下调（均 P<0.05）和 P4 释放减少（AMCs；P=0.01）。PLA 显示在羊膜和绒毛膜细胞中优先的受体-配体结合。P4+CSE 的共同处理并没有逆转 CSE 诱导的作用。总之，P4-PGRMCs 相互作用在整个妊娠期间维持胎膜的功能完整性。增加的 OS 减少了内源性 P4 的产生和细胞类型依赖性的 PGRMCs 下调。这些变化可能导致胎膜特有的“功能性孕酮撤退”，导致在足月和早产条件下出现胎膜功能障碍状态。
