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Plasma Factors in Severe Early-Onset Preeclampsia Do Not Substantially Alter Endothelial Gene Expression In Vitro

Department of Obstetrics and Gynecology, Room Y4.240, Academic Hospital Groningen, Hanz-eplein 1, 9713 GZ Groningen, The Netherlands; r.b.donker{at}og.azg.nl

Sigridur A. Ásgeirsdóttir, PhD

Frans Gerbens, PhD

Maria G. van Pampus, MD, PhD

Cees G. M. Kallenberg, MD, PhD

Gerard J. te Meerman, PhD

Jan G. Aarnoudse, MD, PhD

Grietje Molema, PhD

Departments of Obstetrics and Gynecology, Pathology and Laboratory Medicine, Medical Biology Section, Medical Genetics, and Clinical Immunology, Groningen University Institute for Drug Exploration (GUIDE) and Academic Hospital Groningen, Groningen, The Netherlands.

Objective: Systemic endothelial dysfunction is a central feature in the pathophysiology of preeclanmpsia. Its cell biologic and molecular basis is poorly understood. One leading hypothesis argues that endothelial dysfunction is caused by (at present largely unknown) circulating factors released from the ischemic placenta. This study investigated the effects of plasma factors of severe, early-onset preeclamptic women versus healthy pregnant women on endothelial gene expression in vitro.

Methods: Plasma samples were taken from eight severe early-onset preeclamptic women and eight matched pregnant control women. Primary human umbilical vein endothelial cell (HUVEC) and human glomerular microvascular endothelial cell (hGMEC) cultures were incubated with 20% (vol/vol) plasma for 4, 12, and 24 hours. Identical amounts of RNA isolated from HUVEC from three preeclamptic and three control samples were pooled for each time point, and subsequently hybridized on human 60-mer oligonucleotide microarrays containing 17,000 genes. Gene expression levels of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (CAM-1), interleukin-8 (IL-8), and interleukin-6 (IL-6) in HUVEC and hGMEC were quantfied using real-time reverse transcription polymerase chain reaction (RT-PCR).

Results: Microarray analyses of individual genes identfied no genes that were up-or down-regulated more than 2.7-fold, and analyses of gene ontologies showed no gene ontology signficantly up-or down-regulated in HUVEC by preeclanlptic plasma. IL-8 gene expression was modestly induced by preeclamptic plasma after 4, 12, and 24 hours of HUVEC and hGMEC incubation, as identified by real-time RT-PCR. The other genes analyzed did not show altered regulation by preeclamptic plasma factors.

Conclusions: In vitro, plasma from preeclamptic patients does not substantially alter endothelial gene expression profile. Only modest induction of IL-8 gene expression was observed. These results indicate that mechanisms other than soluble plasma constituents are likely involved in systemic endothelial cell activation in preeclampsia.

Key Words: Preeclampsia • endothelial cell activation • gene expression profiling • plasma factors • interleukin-8

Journal of the Society for Gynecologic Investigation, Vol. 12, No. 2, 98-106 (2005)
DOI: 10.1016/j.jsgi.2004.10.014


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