title: Adenoviral delivery of VEGF121 early in pregnancy prevents spontaneous development of preeclampsia in BPH/5 mice.
abstract: An imbalance in circulating proangiogenic and antiangiogenic factors is postulated to play a causal role in preeclampsia (PE). We have described an inbred mouse strain, BPH/5, which spontaneously develops a PE-like syndrome including late-gestational hypertension, proteinuria, and poor feto-placental outcomes. Here we tested the hypothesis that an angiogenic imbalance during pregnancy in BPH/5 mice leads to the development of PE-like phenotypes in this model. Similar to clinical findings, plasma from pregnant BPH/5 showed reduced levels of free vascular endothelial growth factor (VEGF) and placental growth factor (PGF) compared to C57BL/6 controls. This was paralleled by a marked decrease in VEGF protein and Pgf mRNA in BPH/5 placentae. Surprisingly, antagonism by the soluble form of the FLT1 receptor (sFLT1) did not appear to be the cause of this reduction, as sFLT1 levels were unchanged or even reduced in BPH/5 compared to controls. Adenoviral-mediated delivery of VEGF(121) (Ad-VEGF) via tail vein at embryonic day 7.5 normalized both the plasma-free VEGF levels in BPH/5 and restored the in vitro angiogenic capacity of serum from these mice. Ad-VEGF also reduced the incidence of fetal resorptions and prevented the late-gestational spike in blood pressure and proteinuria observed in BPH/5. These data underscore the importance of dysregulation of angiogenic factors in the pathogenesis of PE and suggest the potential utility of early proangiogenic therapies in treating this disease.
authors.affiliation: Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853-6401, USA.
authors.forename: Ashley K
authors.initials: AK
authors.lastname: Woods
authors.forename: Darren S
authors.initials: DS
authors.lastname: Hoffmann
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Weydert
authors.forename: Scott D
authors.initials: SD
authors.lastname: Butler
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.forename: Ram V
authors.initials: RV
authors.lastname: Sharma
authors.forename: Robin L
authors.initials: RL
authors.lastname: Davisson
mesh_terms: D000256:Adenoviridae; D000818:Animals; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D051379:Mice; D008810:Mice, Inbred C57BL; D010920:Placenta / Q000737:chemistry; D000072483:Placenta Growth Factor; D011225:Pre-Eclampsia / Q000517:prevention & control*; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000097:blood; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000032:analysis
chemical_list: C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1