Placental gene-expression profiles of intrahepatic cholestasis of pregnancy reveal involvement of multiple molecular pathways in blood vessel formation and inflammation

BMC Medical Genomics

JianFeng Chen¹  Tao Duan²  JunLei Wang¹  Ling Lu¹  YaJuan Zheng¹  HaiLong Zhang¹  YouHua Zhang¹  YouDong Pan¹  QiaoLing Du² 

[1]State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China

[2]Department of Obstetrics, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 200040, China

关键词: Immune response;    Genome-wide;    Placenta;    Intrahepatic cholestasis of pregnancy;    Microarray;   

Others  :  1228952
DOI  :  10.1186/1755-8794-7-42

 received in 2013-09-25, accepted in 2014-07-03,  发布年份 2014

【 摘 要 】

Background

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-associated liver disease with potentially deleterious consequences for the fetus, particularly when maternal serum bile-acid concentration >40 μM. However, the etiology and pathogenesis of ICP remain elusive. To reveal the underlying molecular mechanisms for the association of maternal serum bile-acid level and fetal outcome in ICP patients, DNA microarray was applied to characterize the whole-genome expression profiles of placentas from healthy women and women diagnosed with ICP.

Methods

Thirty pregnant women recruited in this study were categorized evenly into three groups: healthy group; mild ICP, with serum bile-acid concentration ranging from 10–40 μM; and severe ICP, with bile-acid concentration >40 μM. Gene Ontology analysis in combination with construction of gene-interaction and gene co-expression networks were applied to identify the core regulatory genes associated with ICP pathogenesis, which were further validated by quantitative real-time PCR and histological staining.

Results

The core regulatory genes were mainly involved in immune response, VEGF signaling pathway and G-protein-coupled receptor signaling, implying essential roles of immune response, vasculogenesis and angiogenesis in ICP pathogenesis. This implication was supported by the observed aggregated immune-cell infiltration and deficient blood vessel formation in ICP placentas.

Conclusions

Our study provides a system-level insight into the placental gene-expression profiles of women with mild or severe ICP, and reveals multiple molecular pathways in immune response and blood vessel formation that might contribute to ICP pathogenesis.

【 授权许可】

   
2014 Du et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Arrese M, Reyes H: Intrahepatic cholestasis of pregnancy: a past and present riddle. Ann Hepatol 2006, 5(3):202-205.
• [2]Arrese M, Macias RI, Briz O, Perez MJ, Marin JJ: Molecular pathogenesis of intrahepatic cholestasis of pregnancy. Expert Rev Mol Med 2008, 10:e9.
• [3]Lausman AY, Al-Yaseen E, Sam D, Nitsch R, Barrett JF, Chan WS: Intrahepatic cholestasis of pregnancy in women with a multiple pregnancy: an analysis of risks and pregnancy outcomes. J Obstet Gynaecol Can 2008, 30(11):1008-1013.
• [4]Beuers U, Pusl T: Intrahepatic cholestasis of pregnancy–a heterogeneous group of pregnancy-related disorders? Hepatology 2006, 43(4):647-649.
• [5]Laatikainen T, Tulenheimo A: Maternal serum bile acid levels and fetal distress in cholestasis of pregnancy. Int J Gynaecol Obstet 1984, 22(2):91-94.
• [6]Glantz A, Marschall HU, Mattsson LA: Intrahepatic cholestasis of pregnancy: Relationships between bile acid levels and fetal complication rates. Hepatology 2004, 40(2):467-474.
• [7]Williamson C, Miragoli M, Sheikh Abdul Kadir S, Abu-Hayyeh S, Papacleovoulou G, Geenes V, Gorelik J: Bile acid signaling in fetal tissues: implications for intrahepatic cholestasis of pregnancy. Dig Dis 2011, 29(1):58-61.
• [8]Colombo C, Zuliani G, Ronchi M, Breidenstein J, Setchell KD: Biliary bile acid composition of the human fetus in early gestation. Pediatr Res 1987, 21(2):197-200.
• [9]Geenes VL, Lim YH, Bowman N, Tailor H, Dixon PH, Chambers J, Brown L, Wyatt-Ashmead J, Bhakoo K, Williamson C: A placental phenotype for intrahepatic cholestasis of pregnancy. Placenta 2011, 32(12):1026-1032.
• [10]Colombo C, Roda A, Roda E, Buscaglia M, Dell’Agnola CA, Filippetti P, Ronchi M, Sereni F: Correlation between fetal and maternal serum bile acid concentrations. Pediatr Res 1985, 19(2):227-231.
• [11]Laatikainen TJ: Fetal bile acid levels in pregnancies complicated by maternal intrahepatic cholestasis. Am J Obstet Gynecol 1975, 122(7):852-856.
• [12]Perez MJ, Macias RI, Marin JJ: Maternal cholestasis induces placental oxidative stress and apoptosis. Protective effect of ursodeoxycholic acid. Placenta 2006, 27(1):34-41.
• [13]Wikstrom Shemer E, Thorsell M, Ostlund E, Blomgren B, Marschall HU: Stereological assessment of placental morphology in intrahepatic cholestasis of pregnancy. Placenta 2012, 33(11):914-918.
• [14]Wei J, Wang H, Yang X, Dong M, Wang Z: Altered gene profile of placenta from women with intrahepatic cholestasis of pregnancy. Arch Gynecol Obstet 2010, 281(5):801-810.
• [15]Cristofalo VJ: A DNA chip off the aging block. Nat Med 2000, 6(5):507.
• [16]Smyth GK: Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 2004, 3:3.
• [17]Saeys Y, Inza I, Larranaga P: A review of feature selection techniques in bioinformatics. Bioinformatics 2007, 23(19):2507-2517.
• [18]Benjamini Y, Hochberg Y: Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. Journal of the Royal Statistical Society Series B Methodological 1995, 57(1):289-300.
• [19]Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM: Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 2000, 25(1):25-29.
• [20]Dupuy D, Bertin N, Hidalgo CA, Venkatesan K, Tu D, Lee D, Rosenberg J, Svrzikapa N, Blanc A, Carnec A, Carvunis AR, Pulak R, Shingles J, Reece-Hoyes J, Hunt-Newbury R, Viveiros R, Mohler WA, Tasan M, Roth FP, Le Peuch C, Hope IA, Johnsen R, Moerman DG, Barabasi AL, Baillie D, Vidal M: Genome-scale analysis of in vivo spatiotemporal promoter activity in Caenorhabditis elegans. Nat Biotechnol 2007, 25(6):663-668.
• [21]Pujana MA, Han JD, Starita LM, Stevens KN, Tewari M, Ahn JS, Rennert G, Moreno V, Kirchhoff T, Gold B, Assmann V, Elshamy WM, Rual JF, Levine D, Rozek LS, Gelman RS, Gunsalus KC, Greenberg RA, Sobhian B, Bertin N, Venkatesan K, Ayivi-Guedehoussou N, Sole X, Hernandez P, Lazaro C, Nathanson KL, Weber BL, Cusick ME, Hill DE, Offit K, et al.: Network modeling links breast cancer susceptibility and centrosome dysfunction. Nat Genet 2007, 39(11):1338-1349.
• [22]Prieto C, Risueno A, Fontanillo C, de las Rivas J: Human gene coexpression landscape: confident network derived from tissue transcriptomic profiles. PLoS One 2008, 3(12):e3911.
• [23]Barabasi AL, Oltvai ZN: Network biology: understanding the cell’s functional organization. Nat Rev Genet 2004, 5(2):101-113.
• [24]Ravasz E, Somera AL, Mongru DA, Oltvai ZN, Barabasi AL: Hierarchical organization of modularity in metabolic networks. Science 2002, 297(5586):1551-1555.
• [25]Carlson MR, Zhang B, Fang Z, Mischel PS, Horvath S, Nelson SF: Gene connectivity, function, and sequence conservation: predictions from modular yeast co-expression networks. BMC Genomics 2006, 7:40.
• [26]Spirin V, Mirny LA: Protein complexes and functional modules in molecular networks. Proc Natl Acad Sci USA 2003, 100(21):12123-12128.
• [27]Floreani A, Caroli D, Lazzari R, Memmo A, Vidali E, Colavito D, D’Arrigo A, Leon A, Romero R, Gervasi M: Intrahepatic Cholestasis Of Pregnancy: New Insights Into Its Pathogenesis. J Matern Fetal Neonatal Med 2013, 26:1410-1415.
• [28]Gleicher N, Elkayam U: Peripartum cardiomyopathy, an autoimmune manifestation of allograft rejection? Autoimmun Rev 2009, 8(5):384-387.
• [29]Gleicher N: Why much of the pathophysiology of preeclampsia-eclampsia must be of an autoimmune nature. Am J Obstet Gynecol 2007., 196(1) 5 e1-7
• [30]Gleicher N, Barad DH: Gestational dermatosis shortly after implantation associated with parental class II HLA compatibility and maternal immune activation: preliminary report of a prospective case series. Dermatology 2011, 222(3):206-211.
• [31]Geva E, Ginzinger DG, Zaloudek CJ, Moore DH, Byrne A, Jaffe RB: Human placental vascular development: vasculogenic and angiogenic (branching and nonbranching) transformation is regulated by vascular endothelial growth factor-A, angiopoietin-1, and angiopoietin-2. J Clin Endocrinol Metab 2002, 87(9):4213-4224.
• [32]Noonan DM, De Lerma BA, Vannini N, Mortara L, Albini A: Inflammation, inflammatory cells and angiogenesis: decisions and indecisions. Cancer Metastasis Rev 2008, 27(1):31-40.
• [33]White AC, Lavine KJ, Ornitz DM: FGF9 and SHH regulate mesenchymal Vegfa expression and development of the pulmonary capillary network. Development 2007, 134(20):3743-3752.
• [34]Hayashi H, Sano H, Seo S, Kume T: The Foxc2 transcription factor regulates angiogenesis via induction of integrin beta3 expression. J Biol Chem 2008, 283(35):23791-23800.
• [35]Luhmann UF, Neidhardt J, Kloeckener-Gruissem B, Schafer NF, Glaus E, Feil S, Berger W: Vascular changes in the cerebellum of Norrin/Ndph knockout mice correlate with high expression of Norrin and Frizzled-4. Eur J Neurosci 2008, 27(10):2619-2628.
• [36]Cao Y, Linden P, Farnebo J, Cao R, Eriksson A, Kumar V, Qi JH, Claesson-Welsh L, Alitalo K: Vascular endothelial growth factor C induces angiogenesis in vivo. Proc Natl Acad Sci U S A 1998, 95(24):14389-14394.
• [37]Karkkainen MJ, Petrova TV: Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis. Oncogene 2000, 19(49):5598-5605.
• [38]Sepúlveda WH GC, Cruz MA, Rudolph MI: Vasoconstrictive effect of bile acids on isolated human placental chorionic veins. Eur J Obstet Gynecol Reprod Biol 1991, 42(3):5.