%0 Journal Article
%T Autocrine activity of soluble Flt-1 controls endothelial cell function and angiogenesis
%A Shakil Ahmad
%A Peter W Hewett
%A Bahjat Al-Ani
%A Samir Sissaoui
%A Takeshi Fujisawa
%A Melissa J Cudmore
%A Asif Ahmed
%J Vascular Cell
%D 2011
%I BioMed Central
%R 10.1186/2045-824x-3-15
%X 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.These results show that endothelial sFlt-1 expression is regulated by VEGF and acts as an autocrine regulator of endothelial cell function.Vascular endothelial growth factor-A (VEGF-A) is a multifunctional cytokine induced by hypoxic stress [1]. It plays a pivotal role in many aspects of embryonic cardiovascular development, including formation of blood vessels, cardiac morphogenesis, and development of the nervous system [2-6]. Loss and gain of function studies in mice indicate that VEGF-A levels have to be maintained within a narrow range to ensure proper cardiovascular development and embryo survival [7-9]. It has been shown that the effects of VEGF-A can be deleterious if uncontrolled. Over-expression of VEGF in experimental animals increases the leakiness of blood vessels, which may lead to severe edema, loss of limb and death [10,11]. Excess VEGF-A expression in skeletal muscle results in the induction of vascular
%U http://www.vascularcell.com/content/3/1/15