Chui A, Murthi P, Gunatillake T, Brennecke S P, Ignjatovic V, Monagle P T, Whitelock J M, Said J M
NorthWest Academic Centre, The University of Melbourne and Sunshine Hospital, PO Box 294, 176 Furlong Road, St Albans 3021, Australia.
Department of Perinatal Medicine, Pregnancy Research Centre, The Royal Women's Hospital, The University of Melbourne, Parkville 3052, Australia; Department of Obstetrics and Gynaecology, The University of Melbourne, Parkville 3052, Australia.
Placenta. 2014 Aug;35(8):596-605. doi: 10.1016/j.placenta.2014.05.009. Epub 2014 Jun 5.
Fetal growth restriction (FGR) is a key cause of adverse pregnancy outcome where maternal and fetal factors are identified as contributing to this condition. Idiopathic FGR is associated with altered vascular endothelial cell functions. Decorin (DCN) has important roles in the regulation of endothelial cell functions in vascular environments. DCN expression is reduced in FGR. The objectives were to determine the functional consequences of reduced DCN in a human microvascular endothelial cell line model (HMVEC), and to determine downstream targets of DCN and their expression in primary placental microvascular endothelial cells (PLECs) from control and FGR-affected placentae.
Short-interference RNA was used to reduce DCN expression in HMVECs and the effect on proliferation, angiogenesis and thrombin generation was determined. A Growth Factor PCR Array was used to identify downstream targets of DCN. The expression of target genes in control and FGR PLECs was performed.
DCN reduction decreased proliferation and angiogenesis but increased thrombin generation with no effect on apoptosis. The array identified three targets of DCN: FGF17, IL18 and MSTN. Validation of target genes confirmed decreased expression of VEGFA, MMP9, EGFR1, IGFR1 and PLGF in HMVECs and PLECs from control and FGR pregnancies.
Reduction of DCN in vascular endothelial cells leads to disrupted cell functions. The targets of DCN include genes that play important roles in angiogenesis and cellular growth. Therefore, differential expression of these may contribute to the pathogenesis of FGR and disease states in other microvascular circulations.
胎儿生长受限（FGR）是不良妊娠结局的关键原因，已确定母体和胎儿因素均促成这一情况。特发性FGR与血管内皮细胞功能改变有关。核心蛋白聚糖（DCN）在血管环境中内皮细胞功能的调节中起重要作用。FGR中DCN表达降低。本研究旨在确定在人微血管内皮细胞系模型（HMVEC）中DCN降低的功能后果，并确定DCN的下游靶点及其在来自对照胎盘和FGR影响胎盘的原代胎盘微血管内皮细胞（PLEC）中的表达。
使用短干扰RNA降低HMVEC中DCN的表达，并确定其对增殖、血管生成和凝血酶生成的影响。使用生长因子PCR阵列鉴定DCN的下游靶点。检测对照和FGR PLEC中靶基因的表达。
DCN表达降低会减少增殖和血管生成，但会增加凝血酶生成，而对细胞凋亡无影响。该阵列鉴定出DCN的三个靶点：FGF17、IL18和MSTN。靶基因验证证实，对照妊娠和FGR妊娠的HMVEC和PLEC中VEGFA、MMP9、EGFR1、IGFR1和PLGF的表达降低。
血管内皮细胞中DCN的减少导致细胞功能紊乱。DCN的靶点包括在血管生成和细胞生长中起重要作用的基因。因此，这些基因的差异表达可能有助于FGR的发病机制以及其他微血管循环中的疾病状态。
