This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 97/12/1253    most recent 01.RES.0000194324.29363.82v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Krysiak, O. Articles by Schönfelder, G. Search for Related Content PubMed PubMed Citation Articles by Krysiak, O. Articles by Schönfelder, G. Related Collections Other hypertension Genetics of cardiovascular disease Gene expression Gene regulation Growth factors/cytokines

(Circulation Research. 2005;97:1253.)
© 2005 American Heart Association, Inc.

Molecular Medicine

Soluble Vascular Endothelial Growth Factor Receptor-1 (sFLT-1) Mediates Downregulation of FLT-1 and Prevents Activated Neutrophils From Women With Preeclampsia From Additional Migration by VEGF

Oliver Krysiak^*, Anja Bretschneider^*, Enhong Zhong, Jessie Webb, Hartmut Hopp, Stefan Verlohren, Norbert Fuhr, Malgorzata Lanowska, Andreas Nonnenmacher, Roland Vetter, Joachim Jankowski, Martin Paul, Gilbert Schönfelder

From the Institute of Clinical Pharmacology and Toxicology (O.K., A.B., E.Z., J.W., R.V., M.P., G.S.) and the Department of Gynecology and Obstetrics (H.H., N.F.), Klinik für Geburtsmedizin, Campus Virshow (S.V.), Medizinische Klinik für Endokrinologie und Nephrologie (J.J.), Charité-Universitaetsmedizin Berlin, Germany.

Correspondence to Dr Gilbert Schönfelder, Institute of Clinical Pharmacology and Toxicology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Garystrasse 5, 14195 Berlin, Germany. E-mail gilbert.schoenfelder{at}charite.de

Neutrophil activation and increased migration is associated with preeclampsia and is resolved after delivery. Preeclampsia is an inflammatory disorder where altered levels of vascular endothelial growth factor (VEGF) and the circulating soluble fms-like tyrosine kinase 1 (sFlt-1) have a pathogenic role. VEGF, by binding to FLT-1, induces leukocytic chemotaxis. We studied expression and function of FLT-1 in maternal neutrophils during preeclampsia and normal pregnancies. Analysis of maternal neutrophils showed the relationship between FLT-1 expression and week of gestation. Preeclamptic women express lower FLT-1 and sFLT-1 in neutrophils. In contrast, serum levels of sFLT-1 in patients with preeclampsia are increased and, therefore, inhibit upregulation of FLT-1 in neutrophils by neutralizing VEGF. VEGF-dependent FLT-1 expression is regulated by changing FLT-1-promoter activity. Promoter activity is decreased by sFLT-1. In vitro experiments demonstrated that migration of neutrophils is regulated by VEGF via FLT-1 and excess of sFLT-1. Thus, VEGF-dependent migration of neutrophils is decreased during preeclampsia as a consequence of excess circulating sFlt1. But, they still increase migration by fMLP and, therefore, migration of neutrophils from preeclamptic women is highly activated when compared with the normotensive group. In conclusion, besides being involved in inducing an antiangiogenic state in the serum, excess of sFLT-1 seems to prevent activated neutrophils from women with preeclampsia from additional migration by VEGF. We provide evidence that neutrophils may be involved in the pathophysiology of pregnancy-related hypertensive disorders.

Key Words: migration • neutrophils • preeclampsia • pregnancy • VEGF receptor 1

This article has been cited by other articles:

				C.-P. Chen, M.-Y. Lee, J.-P. Huang, J. D. Aplin, Y.-H. Wu, C.-S. Hu, P.-C. Chen, H. Li, S.-M. Hwang, S.-H. Liu, et al. Trafficking of Multipotent Mesenchymal Stromal Cells from Maternal Circulation Through the Placenta Involves Vascular Endothelial Growth Factor Receptor-1 and Integrins Stem Cells, February 1, 2008; 26(2): 550 - 561. [Abstract] [Full Text] [PDF]

				V. Muthig, R. Gilsbach, M. Haubold, M. Philipp, T. Ivacevic, M. Gessler, and L. Hein Upregulation of Soluble Vascular Endothelial Growth Factor Receptor 1 Contributes to Angiogenesis Defects in the Placenta of {alpha}2B-Adrenoceptor Deficient Mice Circ. Res., September 28, 2007; 101(7): 682 - 691. [Abstract] [Full Text] [PDF]

				D. Menendez, A. Inga, J. Snipe, O. Krysiak, G. Schonfelder, and M. A. Resnick A Single-Nucleotide Polymorphism in a Half-Binding Site Creates p53 and Estrogen Receptor Control of Vascular Endothelial Growth Factor Receptor 1 Mol. Cell. Biol., April 1, 2007; 27(7): 2590 - 2600. [Abstract] [Full Text] [PDF]

				G. Girardi, D. Yarilin, J. M. Thurman, V. M. Holers, and J. E. Salmon Complement activation induces dysregulation of angiogenic factors and causes fetal rejection and growth restriction J. Exp. Med., September 4, 2006; 203(9): 2165 - 2175. [Abstract] [Full Text] [PDF]

				D. Menendez, O. Krysiak, A. Inga, B. Krysiak, M. A. Resnick, and G. Schonfelder A SNP in the flt-1 promoter integrates the VEGF system into the p53 transcriptional network PNAS, January 31, 2006; 103(5): 1406 - 1411. [Abstract] [Full Text] [PDF]