Department of Obstetrics and Gynecology, Policlinico A. Gemelli, Università Cattolica Del Sacro Cuore, Rome, Italy.
Biol Reprod. 2013 Oct 17;89(4):88. doi: 10.1095/biolreprod.113.109637. Print 2013 Oct.
Celiac disease (CD) is an autoimmune enteropathy triggered by gluten ingestion and characterized by circulating anti-transglutaminase type 2 (anti-TG2) autoantibodies. An epidemiological link between maternal CD and increased risk of pregnancy failure has been established; however, the mechanism underlying this association is still poorly understood. Because proper endometrial angiogenesis and decidualization are prerequisites for placental development, we investigated the effect of anti-TG2 antibodies on the process of endometrial angiogenesis. Binding of anti-TG2 antibodies to human endometrial endothelial cells (HEECs) was evaluated by ELISA. Angiogenesis was studied in vitro on HEECs and in vivo in a murine model. In particular, we investigated the effect of anti-TG2 antibodies on HEEC matrix metalloprotease-2 (MMP-2) activity by gelatin zymography, cytoskeletal organization and membrane properties by confocal microscopy, and activation of extracellular signal-regulated kinases (ERKs) and focal adhesion kinase (FAK) by Western blot analysis. Anti-TG2 antibodies bound to HEECs and decreased newly formed vessels both in vitro and in vivo. Anti-TG2 antibodies impaired angiogenesis by inhibiting the activation of MMP-2, disarranging cytoskeleton fibers, changing the physical and mechanical properties of cell membranes, and inhibiting the intracellular phosphorylation of FAK and ERK. Anti-TG2 antibodies inhibit endometrial angiogenesis affecting the TG2-dependent migration of HEECs and extracellular matrix degradation, which are necessary to form new vessels. Our results identify pathogenic mechanisms of placental damage in CD.
乳糜泻（CD）是一种由麸质摄入引起的自身免疫性肠病，其特征是循环抗转谷氨酰胺酶 2（anti-TG2）自身抗体。已经确立了母体 CD 与妊娠失败风险增加之间的流行病学联系；然而，这种关联的机制仍知之甚少。因为适当的子宫内膜血管生成和蜕膜化是胎盘发育的前提条件，所以我们研究了抗 TG2 抗体对子宫内膜血管生成过程的影响。通过 ELISA 评估抗 TG2 抗体与人子宫内膜内皮细胞（HEEC）的结合。在体外研究了 HEEC 中的血管生成，并在小鼠模型中进行了体内研究。特别是，我们通过明场显微镜研究了抗 TG2 抗体对 HEEC 基质金属蛋白酶-2（MMP-2）活性的影响，通过共聚焦显微镜研究了细胞骨架组织和膜特性的影响，通过 Western blot 分析研究了细胞外信号调节激酶（ERK）和粘着斑激酶（FAK）的激活。抗 TG2 抗体与 HEEC 结合，并在体外和体内均减少新形成的血管。抗 TG2 抗体通过抑制 MMP-2 的激活、扰乱细胞骨架纤维、改变细胞膜的物理和机械特性以及抑制粘着斑激酶（FAK）和细胞外信号调节激酶（ERK）的细胞内磷酸化来抑制血管生成。抗 TG2 抗体抑制子宫内膜血管生成，影响 TG2 依赖性 HEEC 迁移和细胞外基质降解，这是形成新血管所必需的。我们的结果确定了 CD 中胎盘损伤的发病机制。
