Department of Reproductive Immunology and Pathology, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland.
Biol Reprod. 2022 Dec 10;107(6):1503-1516. doi: 10.1093/biolre/ioac163.
A molecular interaction between maternal endometrium and implanting conceptus can lead to activation of a variety of transcription factors that regulate expression of several genes necessary for the process of embryo implantation. While, signal transducer and activator of transcription 3 (STAT3) is responsible for decidualization and epithelial remodeling in humans and mice, its role in porcine endometrium has not been explored before. In the present study, we observed a pregnancy dependent increase in gene and protein expression of STAT3. Phosphorylated STAT3 was predominantly present in the endometrium of pregnant animals in luminal and glandular epithelium and in the endothelium of blood vessels with a weak staining in stromal cells. Interleukins, IL-1β and IL-6, and epidermal growth factor (EGF)-induced STAT3 expression and phosphorylation in endometrial explants collected on Day 13 of the estrous cycle. Biological significance of STAT3 was evaluated by blocking its phosphorylation with STAT3-specific inhibitor, Stattic. Using porcine extracellular matrix (ECM) and adhesion molecule array, EGF was shown to induce changes in gene expression of ECM components: MMP1, MMP3, MMP12, LAMA1, SELL, and ICAM1, which was abrogated in the presence of Stattic. Transcriptional activity of STAT3 was observed in promoter regions of MMP3 and MMP12. Additionally, IL-6-induced STAT3 phosphorylation upregulated VEGF and VCAM1 abundances in endometrial-endothelial cells (EEC). Moreover, IL-6 resulted in an increase in EEC proliferation and capillary formation which was reversed in the presence of Stattic. Results of present study reveal a role for STAT3 phosphorylation in regulating extracellular matrix remodeling and angiogenesis in porcine endometrium to facilitate embryo implantation.
母体子宫内膜与着床胚胎之间的分子相互作用可导致多种转录因子的激活，这些转录因子调节胚胎着床过程中几种基因的表达。而信号转导和转录激活因子 3（STAT3）负责人类和小鼠的蜕膜化和上皮重塑，但其在猪子宫内膜中的作用尚未被探索。在本研究中，我们观察到妊娠依赖的 STAT3 基因和蛋白表达增加。磷酸化 STAT3 主要存在于妊娠动物的子宫内膜腔上皮和腺上皮以及血管内皮中，基质细胞中染色较弱。白细胞介素（IL）-1β和 IL-6 以及表皮生长因子（EGF）可诱导发情周期第 13 天采集的子宫内膜外植体中 STAT3 的表达和磷酸化。通过使用 STAT3 特异性抑制剂 Stattic 阻断 STAT3 的磷酸化来评估 STAT3 的生物学意义。使用猪细胞外基质（ECM）和粘附分子阵列，结果表明 EGF 诱导 ECM 成分的基因表达发生变化：MMP1、MMP3、MMP12、LAMA1、SELL 和 ICAM1，而在 Stattic 存在下这种变化被阻断。在 MMP3 和 MMP12 的启动子区域观察到 STAT3 的转录活性。此外，IL-6 诱导的 STAT3 磷酸化可上调子宫内膜内皮细胞（EEC）中 VEGF 和 VCAM1 的丰度。此外，IL-6 导致 EEC 增殖和毛细血管形成增加，而在 Stattic 存在下则逆转了这种增加。本研究的结果表明，STAT3 磷酸化在调节猪子宫内膜中细胞外基质重塑和血管生成以促进胚胎着床中发挥作用。
