title: The perinatal implications of angiogenic factors.
abstract: OBJECTIVE
  To summarize recent findings relating maternal circulating levels of proteins associated with angiogenesis and the outcome of pregnancy.
  
  
  RESULTS
  In preeclampsia, levels of placental growth factor (PlGF) become abnormal prior to soluble fms-like tyrosine kinase 1 (sFlt-1). Longitudinal measurement of changes in protein level are better predictors of disease than measurement at a single time point in pregnancy and also appear to be more strongly associated with early-onset disease. The levels of angiogenic proteins provide additional predictive information over abnormal uteroplacental Doppler. The preeclampsia-like phenotype of rats overexpressing sFlt-1 can be ameliorated by administration of a protein which binds and inactivates sFlt-1. Animal models demonstrate that uteroplacental ischemia leads to elevated maternal serum levels of sFlt-1 and decreased PlGF. Similarly, studies of human trophoblast cells demonstrate that hypoxia stimulates release of sFlt-1. Autocrine vascular endothelial growth factor (VEGF) has a trophic effect on the endothelium, distinct from its control of angiogenesis. By blocking this effect, elevated sFlt-1 could lead to systemic endothelial cell dysfunction, one of the key features of preeclampsia. Low levels of PlGF are associated with intrauterine growth restriction. However, in the first trimester of pregnancy, high levels of sFlt-1 were associated with reduced rates of growth restriction, preterm birth and stillbirth.
  
  
  CONCLUSIONS
  Regulators of the VEGF system may have a causal role in the sequence of events leading to preeclampsia and may be targets for novel therapies. However, better knowledge of the biology is required prior to clinical trials of interventions.
authors.affiliation: Department of Obstetrics and Gynaecology, Cambridge University and NIHR Cambridge Comprehensive Biomedical Research Centre, Cambridge, UK. gcss2@cam.ac.uk
authors.forename: Gordon C S
authors.initials: GC
authors.lastname: Smith
authors.forename: Helen
authors.initials: H
authors.lastname: Wear
mesh_terms: D000818:Animals; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D000860:Hypoxia; D023421:Models, Animal; D018919:Neovascularization, Physiologic; D000072483:Placenta Growth Factor; D011247:Pregnancy; D011256:Pregnancy Outcome; D011257:Pregnancy Proteins / Q000096:biosynthesis; D012307:Risk Factors; D014327:Trophoblasts / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis
chemical_list: C000608036:PGF protein, human; C000608038:Pgf protein, rat; D011257:Pregnancy Proteins; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1