Soluble FLT1 sensitizes endothelial cells to inflammatory cytokines by antagonizing VEGF receptor-mediated signalling
Open Access
- 7 December 2010
- journal article
- research article
- Published by Oxford University Press (OUP) in Cardiovascular Research
- Vol. 89 (3), 671-679
- https://doi.org/10.1093/cvr/cvq346
Abstract
Pre-eclampsia affects 5–7% of pregnancies, and is a major cause of maternal and foetal death. Elevated serum levels of placentally derived splice variants of the vascular endothelial growth factor (VEGF) receptor, soluble fms-like tyrosine kinase-1 (sFLT1), are strongly implicated in the pathogenesis but, as yet, no underlying mechanism has been described. An excessive inflammatory-like response is thought to contribute to the maternal endothelial cell dysfunction that characterizes pre-eclampsia. We hypothesized that sFLT1 antagonizes autocrine VEGF-A signalling, rendering endothelial cells more sensitive to pro-inflammatory factors also released by the placenta. We tested this by manipulating VEGF receptor signalling and treating endothelial cells with low doses of tumour necrosis factor-α (TNF-α). Application of recombinant sFLT1 alone did not activate human umbilical vein endothelial cells (HUVECs). However, antagonizing the autocrine actions of endothelial VEGF-A and/or placenta growth factor (PlGF) by pre-incubation with recombinant sFLT1, anti-FLT1, anti-VEGF receptor 2 (KDR), anti-VEGF-A, VEGF receptor tyrosine kinase inhibitor SU5614, or knocking-down FLT1 or KDR transcripts rendered cells more sensitive to low doses of TNF-α. Each treatment increased activation, as measured by increases in endothelial intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), endothelin 1 (ET-1), von Willebrand factor (vWF), and leucocyte adhesion, and led to reduction in AKT Ser473 and endothelial nitric oxide synthase (eNOS) Ser1177 phosphorylation. Our data describe a mechanism by which sFLT1 sensitizes endothelial cells to pro-inflammatory factors, providing an explanation for how placental stress may precipitate the pre-eclamptic syndrome.Keywords
This publication has 33 references indexed in Scilit:
- Inhaled Nitric Oxide Decreases Leukocyte Trafficking in the Neonatal Mouse Lung During Exposure to >95% OxygenPediatric Research, 2010
- Novel Splice Variants of sFlt1 are Upregulated in PreeclampsiaPlacenta, 2009
- Nitric Oxide Formation Is Inversely Related to Serum Levels of Antiangiogenic Factors Soluble Fms-Like Tyrosine Kinase-1 and Soluble Endogline in PreeclampsiaHypertension, 2008
- VEGF Inhibition and Renal Thrombotic MicroangiopathyThe New England Journal of Medicine, 2008
- Oxidative Stress, Gene Expression, and Protein Changes Induced in the Human Placenta during LaborThe American Journal of Pathology, 2007
- Autocrine VEGF Signaling Is Required for Vascular HomeostasisCell, 2007
- Soluble Endoglin and Other Circulating Antiangiogenic Factors in PreeclampsiaThe New England Journal of Medicine, 2006
- Neutrophils Infiltrate Resistance-Sized Vessels of Subcutaneous Fat in Women With PreeclampsiaHypertension, 2004
- Circulating Angiogenic Factors and the Risk of PreeclampsiaThe New England Journal of Medicine, 2004
- Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor.Proceedings of the National Academy of Sciences of the United States of America, 1993