Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Preeclampsia leads to dysregulation of various signaling pathways in placenta Jin Hee Kang a,1 , Haengseok Song b,1 , Jung Ah Yoon b , Dong Yoon Park c , Sung Han Kim c , Kyoung Jin Lee a , Antonio Farina d , Yeon Kyung Cho a , Young Nam Kim e , Sang Won Park a , Gi Jin Kim b , Sung Han Shim b and Dong Hyun Cha a Objectives To compare gene expression profiles of placentas from preeclamptic and normal pregnancies. Study design We performed microarray experiments to analyze genome-wide expression profiling for 10 placentas from pregnant women with preeclampsia and 10 placentas from women who experienced noncomplicated pregnancies (CON), and to identify dysregulated signaling pathways as well as genes in preeclampsia. RT-PCR, real- time RT-PCR and/or immunofluorescence analyses were performed to validate the data obtained from microarray experiments. Results Unsupervised hierarchical clustering showed heterogeneity of preeclampsia at the molecular levels, whereas expression profiles of preeclampsia are distinctly different from those of CON. A list of genes which are differentially expressed between preeclampsia and CON included well known preeclampsia markers, such as Flt-1, leptin, HTRA1 and SIGLEC6. Gene Set Enrichment Analysis, a pathway-oriented analysis method for expression profiles, provided evidence that a number of biological activities including pathways that regulate actin cytoskeleton, TGFb signaling, oxidative phosphorylation, and proteasome activity were aberrantly either up-regulated or down- regulated in preeclampsia. RT-PCR and real-time-RT-PCR for genes contributing these biological pathways (gene sets) enriched in either CON or preeclampsia reinforced that these biological processes were systemically dysregulated in preeclampsia. Conclusions Genome-wide expression profiles of preeclampsia showed heterogeneous characteristics of preeclampsia at the molecular levels. Dysregulation of genes and biological pathways could contribute to abnormal behavior of preeclmapsia. Our results will help further understand underlying mechanisms by which preeclampsia affects placental physiology. J Hypertens 29:928–936 Q 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins. Journal of Hypertension 2011, 29:928–936 Keywords: gene, hypertension, microarray, placenta, preeclampsia, signaling pathway a Department of Obstetrics and Gynecology, CHA Hospital, CHA University, b Department of Biomedical Science, CHA University, c Digital Genomics Inc., Seoul, Korea, d Division of Prenatal Medicine, Department of Human Embryology, University of Bologna, Bologna, Italy and e Department of Obstetrics and Gynecology, Pusan Baik Hospital, Inje University, Busan, Korea Correspondence to Dong Hyun Cha, MD, Department of Obstetrics and Gynecology, CHA hospital, CHA University, 650-9 Yeok sam-1 dong, Kangnam- gu, Seoul 135-081, Korea Tel: +82 2 3468 3123; fax: +82 2 558 1119; e-mail: chadh001@hanmail.net Received 6 April 2010 Revised 13 December 2010 Accepted 14 January 2011 Introduction Preeclampsia is a major cause of maternal and fetal mortality and morbidity. Occurring in 4–8% of pregnan- cies [1,2], this multisystemic disorder contributes to 16% of maternal deaths in developed countries [3]. Despite decades of research, the underlying pathogenesis of pre- eclampsia remains elusive, and the development of reliable predictors, specific preventive measures, and therapeutic interventions are concurrently hindered. Several theories have been proposed, including defective placental vascular remodeling early in pregnancy [4], genetic polymorphism [5], immune maladaptation [6], vascular endothelial cell dysfunction [7], and exagger- ation of systemic inflammatory disease [8]. The most widely accepted theory is that the placenta, in response to ischemic hypoxia and oxidative stress associated caused by poor placental perfusion, releases factors into the circulation producing excessive maternal systemic inflammation. The resulting generalized endothelial dys- function with systemic inflammatory response is accepted as the final common pathway that leads to the maternal characteristic signs of preeclampsia with hypertension and proteinuria in the late period of preg- nancy [9,10]. Placental microarray studies provide opportunities to confirm or refute evidence for involvement of previous described candidate genes in preeclampsia, while iden- tifying potential novel candidate genes by means of global genomic variations. To date, several studies have assessed gene expression profiles from preeclamptic 928 Original article 1 Jin Hee Kang and Haengseok Song contributed equally to the writing of this article. 0263-6352 ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/HJH.0b013e328344a82c