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

TLDR

Vascular endothelial growth factor drives angiogenesis and endothelial integrity, is elevated in tumors and pre‑eclampsia, and its regulation by an antagonist is essential for successful pregnancy. The authors used in situ hybridization, heparin affinity, column fractionation, and cross‑linking to demonstrate that trophoblasts express and secrete soluble VEGF receptor sFlt‑1. Binding assays, Western blotting, and serum analyses show that the placenta secretes soluble VEGF receptor sFlt‑1, a VEGF antagonist, marking the first in vivo report of its production and highlighting its potential impact on VEGF activity in pregnancy and other conditions.

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.