A Chui1, P Murthi2, T Gunatillake3, S P Brennecke2, V Ignjatovic4, P T Monagle4, J M Whitelock5, J M Said6. 1. NorthWest Academic Centre, The University of Melbourne and Sunshine Hospital, PO Box 294, 176 Furlong Road, St Albans 3021, Australia. Electronic address: akl.chui83@gmail.com. 2. 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. 3. NorthWest Academic Centre, The University of Melbourne and Sunshine Hospital, PO Box 294, 176 Furlong Road, St Albans 3021, Australia; Department of Obstetrics and Gynaecology, The University of Melbourne, Parkville 3052, Australia. 4. Murdoch Children's Research Institute, The Royal Children's Hospital and The University of Melbourne, Parkville 3052, Australia; Department of Clinical Haematology, The Royal Children's Hospital and The University of Melbourne, Parkville 3052, Australia; Department of Paediatrics, The Royal Children's Hospital and The University of Melbourne, Parkville 3052, Australia. 5. Graduate School of Biomedical Engineering, University of New South Wales, Kensington 2033, Australia. 6. NorthWest Academic Centre, The University of Melbourne and Sunshine Hospital, PO Box 294, 176 Furlong Road, St Albans 3021, Australia.
Abstract
OBJECTIVE: 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. APPROACH: 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. RESULTS: 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. CONCLUSIONS: 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.
OBJECTIVE: 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. APPROACH: 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. RESULTS: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. CONCLUSIONS: 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.
Authors: Amy K L Chui; Tilini N Gunatillake; Vera Ignjatovic; Paul T Monagle; Padma Murthi; Shaun P Brennecke; John M Whitelock; Joanne M Said Journal: Blood Adv Date: 2017-07-03
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Authors: Benjamin M Ellingson; Kunal Patel; Chencai Wang; Catalina Raymond; Andrew Brenner; John F de Groot; Nicholas A Butowski; Leor Zach; Jian L Campian; Jacob Schlossman; Shan Rizvi; Yael C Cohen; Noa Lowenton-Spier; Tamar Rachmilewitz Minei; Shifra Fain Shmueli; Patrick Y Wen; Timothy F Cloughesy Journal: Neurooncol Adv Date: 2021-06-19