A Vascular Endothelial Growth Factor Antagonist Is Produced by the Human Placenta and Released into the Maternal Circulation1

Abstract

Vascular endothelial growth factor (VEGF) is a potent secreted factor that promotes angiogenesis and maintains the integrity of the endothelium. Levels of VEGF are increased in many tumors and are elevated in women with pre-eclampsia, a serious disease of pregnancy. Here we show by in situ hybridization that the trophoblast contains the mRNA encoding a soluble version of the VEGF receptor known as Flt-1 (sFlt-1: initially described by Kendall and Thomas, PNAS 90:10705-10709). Binding assays and Western blotting of villus-conditioned media confirmed the production of sFlt-1. Serum from pregnant women was found to contain a VEGF-binding protein that was not present in serum from men or nonpregnant women. As determined by heparin affinity, column fractionation, and cross-linking, this protein was identical to sFlt-1. Taken together, these results show that the placenta secretes sFlt-1, which would be expected to be a VEGF antagonist. This is the first report of production of the sFlt-1 receptor in vivo, and it reveals a new mechanism for naturally regulating this potent angiogenic agent. The presence of such an antagonist suggests that regulation of VEGF action is essential to successful pregnancy. This has important implications for the activity of VEGF locally and systemically in other conditions.

A Maternally Sequestered, Biopolymer‐Stabilized Vascular Endothelial Growth Factor (VEGF) Chimera for Treatment of Preeclampsia

“…VEGF‐A has been shown to stimulate the expression of sFlt‐1 by regulating the alternative splicing of the Flt‐1 gene94 in both in vascular endothelial cells and human placental explants 65, 95. VEGF‐A binds to the VEGFR2 receptor, and by protein kinase C (PKC)–MEK signaling, acts on the VEGF‐A Response Element on Intron 13 of the VEGFR1 gene 94.…”

“…Building on the therapeutic potential of a biopolymer‐stabilized VEGF chimera in treating placental ischemia, future studies will also involve evaluation of other therapeutics to target and reduce the bioavailability of sFlt‐1. VEGF‐B and placental growth factor also bind to sFlt‐1,102 and unlike VEGF‐A, do not bind to the main angiogenic receptor VEGFR2, which reduces their risk of adverse effects because of aberrant angiogenesis 37, 38, 65. We are currently testing ELP–placental growth factor and ELP‐VEGF‐B fusion proteins.…”

Magnesium sulfate therapy of preeclampsia: an old tool with new mechanism of action and prospect in management and prophylaxis

“…6 This report supports the hypothesis that these factors are a cause and not only a result of the endothelial dysfunction in the major body organs, causing proteinuria, hypertension and the rest of the systemic manifestations of the disease. 8,9 VEGF has been reported to augment nitric oxide (NO) production through VEGFR-2/ the kinase domain receptor, 10 and NO was found to have an important role in the mitogenic effect of VEGF during angiogenesis. 11 However, little is known about the relation between circulating VEGF and NO levels in PE.…”

Identification of the high-risk group for metastasis of gastric cancer cases by vascular endothelial growth factor receptor-1 overexpression in peripheral blood

“…The sVEGFR1 competitively inhibits the binding between VEGFR1 and its ligands, such as VEGF and PGF. Moreover, Clark et al (1998) reported that sVEGFR1 exists specifically in serum from pregnant women, and does not exist in serum from men and nonpregnant women. For that reason we did not assess sVEGFR1 protein in this study.…”