title: Autocrine activity of soluble Flt-1 controls endothelial cell function and angiogenesis.
abstract: BACKGROUND
  The negative feedback system is an important physiological regulatory mechanism controlling angiogenesis. Soluble vascular endothelial growth factor (VEGF) receptor-1 (sFlt-1), acts as a potent endogenous soluble inhibitor of VEGF- and placenta growth factor (PlGF)-mediated biological function and can also form dominant-negative complexes with competent full-length VEGF receptors.
  
  
  RESULTS
  Systemic overexpression of VEGF-A in mice resulted in significantly elevated circulating sFlt-1. In addition, stimulation of human umbilical vein endothelial cells (HUVEC) with VEGF-A, induced a five-fold increase in sFlt-1 mRNA, a time-dependent significant increase in the release of sFlt-1 into the culture medium and activation of the flt-1 gene promoter. This response was dependent on VEGF receptor-2 (VEGFR-2) and phosphoinositide-3'-kinase signalling. siRNA-mediated knockdown of sFlt-1 in HUVEC stimulated the activation of endothelial nitric oxide synthase, increased basal and VEGF-induced cell migration and enhanced endothelial tube formation on growth factor reduced Matrigel. In contrast, adenoviral overexpression of sFlt-1 suppressed phosphorylation of VEGFR-2 at tyrosine 951 and ERK-1/-2 MAPK and reduced HUVEC proliferation. Preeclampsia is associated with elevated placental and systemic sFlt-1. Phosphorylation of VEGFR-2 tyrosine 951 was greatly reduced in placenta from preeclamptic patients compared to gestationally-matched normal placenta.
  
  
  CONCLUSIONS
  These results show that endothelial sFlt-1 expression is regulated by VEGF and acts as an autocrine regulator of endothelial cell function.
authors.affiliation: University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
authors.forename: Shakil
authors.initials: S
authors.lastname: Ahmad
authors.affiliation: Department of Reproductive and Vascular Biology, Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, B15 2TT, UK.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Hewett
authors.affiliation: Department of Reproductive and Vascular Biology, Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, B15 2TT, UK.
authors.forename: Bahjat
authors.initials: B
authors.lastname: Al-Ani
authors.affiliation: Department of Reproductive and Vascular Biology, Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, B15 2TT, UK.
authors.forename: Samir
authors.initials: S
authors.lastname: Sissaoui
authors.affiliation: University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Fujisawa
authors.affiliation: University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Cudmore
authors.affiliation: University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.|Department of Reproductive and Vascular Biology, Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, B15 2TT, UK.
authors.forename: Asif
authors.initials: A
authors.lastname: Ahmed