title: 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.
abstract: 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.
authors.affiliation: Institute of Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Krysiak
authors.forename: Anja
authors.initials: A
authors.lastname: Bretschneider
authors.forename: Enhong
authors.initials: E
authors.lastname: Zhong
authors.forename: Jessie
authors.initials: J
authors.lastname: Webb
authors.forename: Hartmut
authors.initials: H
authors.lastname: Hopp
authors.forename: Stefan
authors.initials: S
authors.lastname: Verlohren
authors.forename: Norbert
authors.initials: N
authors.lastname: Fuhr
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Lanowska
authors.forename: Andreas
authors.initials: A
authors.lastname: Nonnenmacher
authors.forename: Roland
authors.initials: R
authors.lastname: Vetter
authors.forename: Joachim
authors.initials: J
authors.lastname: Jankowski
authors.forename: Martin
authors.initials: M
authors.lastname: Paul
authors.forename: Gilbert
authors.initials: G
authors.lastname: Schönfelder
mesh_terms: D002465:Cell Movement; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D006801:Humans; D018375:Neutrophil Activation; D009504:Neutrophils / Q000737:chemistry / Q000502:physiology*; D011225:Pre-Eclampsia / Q000097:blood*; D011247:Pregnancy; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood / Q000235:genetics / Q000502:physiology*
chemical_list: D042461:Vascular Endothelial Growth Factor A; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1