Department of Obstetrics and Gynecology, Medical University of Graz, Auenbruggerplatz 14, 8036 Graz, Austria.
J Clin Endocrinol Metab. 2012 Oct;97(10):3613-21. doi: 10.1210/jc.2012-1212. Epub 2012 Aug 14.
Gestational diabetes mellitus (GDM)-associated hormonal and metabolic derangements in mother and fetus affect placental development and function. Indeed, in GDM, placentas are characterized by hypervascularization and vascular dysfunction. The membrane-type matrix metalloproteinase 1 (MT1-MMP) is a key player in angiogenesis and vascular expansion.
Here, we hypothesized elevated placental MT1-MMP levels in GDM induced by components of the diabetic environment. Therefore, we measured placental MT1-MMP in normal vs. GDM pregnancies, identified potential functional consequences, and investigated the contribution of hyperglycemia and the insulin/IGF axis.
Immunohistochemistry identified placental cell types expressing MT1-MMP. MT1-MMP was compared between normal and GDM placentas by immunoblotting. Quantitative PCR of MT1-MMP in primary feto-placental endothelial cells (fpEC) and trophoblasts isolated from both normal and GDM placentas identified the cells contributing to the GDM-associated changes. A putative MT1-MMP role in angiogenesis was determined using blocking antibodies for in vitro angiogenesis assays. Potential GDM-associated factors and signaling pathways inducing MT1-MMP up-regulation in fpEC were identified using kinase inhibitors.
Total and active MT1-MMP was increased in GDM placentas (+51 and 54%, respectively, P<0.05) as a result of up-regulated expression in fpEC (2.1-fold, P=0.02). MT1-MMP blocking antibodies reduced in vitro angiogenesis up to 25% (P=0.03). Pathophysiological levels of insulin and IGF-II, but not IGF-I and glucose, stimulated MT1-MMP expression in fpEC by phosphatidylinositol 3-kinase signals relayed through the insulin, but not IGF-I, receptor.
GDM up-regulates MT1-MMP in the feto-placental endothelium, and insulin and IGF-II contribute. This may account for GDM-associated changes in the feto-placental vasculature.
妊娠糖尿病（GDM）相关的母体和胎儿的激素和代谢紊乱会影响胎盘的发育和功能。事实上，在 GDM 中，胎盘的特征是血管过度生长和血管功能障碍。膜型基质金属蛋白酶 1（MT1-MMP）是血管生成和血管扩张的关键因子。
我们假设糖尿病环境的成分会导致 GDM 中胎盘 MT1-MMP 水平升高。因此，我们测量了正常妊娠和 GDM 妊娠中胎盘 MT1-MMP 的水平，确定了潜在的功能后果，并研究了高血糖和胰岛素/IGF 轴的贡献。
免疫组织化学鉴定了表达 MT1-MMP 的胎盘细胞类型。通过免疫印迹比较了正常和 GDM 胎盘之间的 MT1-MMP。从正常和 GDM 胎盘分离的原代胎-胎盘内皮细胞（fpEC）和滋养层细胞中进行 MT1-MMP 的定量 PCR，确定了导致 GDM 相关变化的细胞。使用阻断抗体进行体外血管生成实验，确定 MT1-MMP 在血管生成中的潜在作用。使用激酶抑制剂鉴定潜在的 GDM 相关因素和信号通路，以诱导 fpEC 中 MT1-MMP 的上调。
GDM 胎盘中的总 MT1-MMP 和活性 MT1-MMP 分别增加了 51%和 54%（均 P<0.05），这是由于 fpEC 中的表达上调（2.1 倍，P=0.02）。MT1-MMP 阻断抗体可使体外血管生成减少高达 25%（P=0.03）。胰岛素和 IGF-II 的病理生理水平，但不是 IGF-I 和葡萄糖，通过胰岛素受体而不是 IGF-I 受体传递的磷脂酰肌醇 3-激酶信号刺激 fpEC 中的 MT1-MMP 表达。
GDM 在胎-胎盘内皮细胞中上调 MT1-MMP，胰岛素和 IGF-II 有贡献。这可能解释了 GDM 相关的胎-胎盘血管变化。
