Altered decorin leads to disrupted endothelial cell function: A possible mechanism in the pathogenesis of fetal growth restriction?

• Published in: Placenta (Eastbourne) 2014-08, Vol.35 (8), p.596-605
• Main Authors: Chui, A, Murthi, P, Gunatillake, T, Brennecke, S.P, Ignjatovic, V, Monagle, P.T, Whitelock, J.M, Said, J.M
• Format: Article
• Language: English
• Subjects: Angiogenesis; Apoptosis; Biological and medical sciences; Case-Control Studies; Cell Line; Cell Proliferation; Decorin - metabolism; Embryology: invertebrates and vertebrates. Teratology; Endothelial Cells - metabolism; Endothelial function; Female; Fetal Growth Retardation - etiology; Fetal Growth Retardation - metabolism; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation; Humans; Internal Medicine; Obstetrics and Gynecology; Placenta - metabolism; Pregnancy; Regulation; RNA, Small Interfering; Thrombin - metabolism; Thrombosis
• ISSN: 0143-4004; 1532-3102
• DOI: 10.1016/j.placenta.2014.05.009

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.