Autocrine activity of soluble Flt-1 controls endothelial cell function and angiogenesis

Ahmad, Shakil, Hewett, Peter W., Al-Ani, Bahjat, Sissaoui, Samir, Fujisawa, Takeshi, Cudmore, Melissa J. and Ahmed, Asif (2011). Autocrine activity of soluble Flt-1 controls endothelial cell function and angiogenesis. Vascular Cell, 3 (1),

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. Methods and 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. Conclusion - These results show that endothelial sFlt-1 expression is regulated by VEGF and acts as an autocrine regulator of endothelial cell function.

Publication DOI: https://doi.org/10.1186/2045-824X-3-15
Divisions: Life & Health Sciences > Biosciences
Life & Health Sciences
Aston Medical School
Additional Information: © 2011 Ahmad et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Uncontrolled Keywords: Cell Biology,Computer Networks and Communications,Neurology,Developmental Neuroscience
Full Text Link: http://www.vasc ... /content/3/1/15
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
Published Date: 2011-07-13
Authors: Ahmad, Shakil ( 0000-0002-9294-0475)
Hewett, Peter W.
Al-Ani, Bahjat
Sissaoui, Samir
Fujisawa, Takeshi
Cudmore, Melissa J.
Ahmed, Asif

Download

[img]

Version: Published Version


Export / Share Citation


Statistics

Additional statistics for this record