A vascular endothelial growth factor antagonist is produced by the human placenta and released into the maternal circulation.
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.
Clark
D E
DE
a Reproductive Molecular Research Group, Department of Obstetrics and Gynaecology, University of Cambridge, The Rosie Hospital, CB2 2SW, United Kingdom.
Smith
S K
SK
He
Y
Y
Day
K A
KA
Licence
D R
DR
Corps
A N
AN
Lammoglia
R
R
Charnock-Jones
D S
DS
D015153:Blotting, Western; D002846:Chromatography, Affinity; D003432:Cross-Linking Reagents; D017077:Culture Media, Conditioned; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007457:Iodine Radioisotopes; D008222:Lymphokines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010920:Placenta / Q000098:blood supply / Q000378:metabolism*; D011247:Pregnancy; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000097:blood* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000097:blood* / Q000235:genetics; D012995:Solubility; D014327:Trophoblasts / Q000737:chemistry; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors
D003432:Cross-Linking Reagents; D017077:Culture Media, Conditioned; D016228:Endothelial Growth Factors; D007457:Iodine Radioisotopes; D008222:Lymphokines; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040281:Vascular Endothelial Growth Factor Receptor-1