title: Trophoblast-specific reduction of VEGFA alters placental gene expression and maternal cardiovascular function in mice.
abstract: Given the angiogenic function of vascular endothelial growth factor A (VEGFA), the function of its expression by trophoblast in the avascular placental junctional zone is unknown. In mice, cells from the trophoblast-specific protein alpha (Tpbpa) lineage populate this zone and, in late gestation, some of these cells invade the decidual layer. To diminish Vegfa expression in Tpbpa cells, we crossed Vegfa(flox/flox) females with males carrying Tpbpa-Cre. For single deletion (sd) of Vegfa in Tpbpa cells in 100% of conceptuses (SD100 pregnancies, sd conceptuses) we crossed homozygous lines. For double deletion (dd) of both Vegfa alleles in 50% of the conceptuses (DD50 pregnancies, 50% dd conceptuses and 50% no deletion [nd]), we crossed homozygous Vegfa(flox/flox) females with males heterozygous for Tpbpa-Cre and homozygous for Vegfa(flox/flox). Controls were Vegfa(flox/flox) females bred to wild-type males (V-CTRL pregnancies). In SD100 pregnancies, maternal plasma immunoreactive VEGFA significantly increased and arterial blood pressure decreased, whereas fetal body weight and placental Flt1, sFlt1, and Prl3b1 mRNA were unchanged. In DD50, maternal immunoreactive VEGFA and arterial pressures were unaltered, but both dd and nd conceptuses exhibited significantly increased embryonic lethality, altered expression of Flt1, sFlt1, and Prl3b1 mRNA in the decidual layer, and decreased fetal body weight relative to V-CTRL. Maternal cardiac output significantly increased in proportion to dd conceptuses in the pregnancy. In DD50, results are consistent with altered maternal function beginning in early gestation and adversely impacting both conceptus genotypes. We conclude that maternal function is influenced by Vegfa expression in trophoblast cells at the maternal-fetal interface, likely via an endocrine mechanism.
authors.affiliation: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Han
authors.initials: H
authors.lastname: Li
authors.affiliation: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Dawei
authors.initials: D
authors.lastname: Qu
authors.affiliation: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Angela
authors.initials: A
authors.lastname: McDonald
authors.affiliation: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Isaac
authors.affiliation: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Kathie J
authors.initials: KJ
authors.lastname: Whiteley
authors.affiliation: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Hoon-Ki
authors.initials: HK
authors.lastname: Sung
authors.affiliation: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Andras
authors.initials: A
authors.lastname: Nagy
authors.affiliation: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada Department of Physiology, University of Toronto, Toronto, Ontario, Canada Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada adamson@lunenfeld.ca.
authors.forename: S Lee
authors.initials: SL
authors.lastname: Adamson
mesh_terms: D000818:Animals; D019070:Cell Lineage; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000502:physiology; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D008431:Maternal-Fetal Exchange; D051379:Mice; D008822:Mice, Transgenic; D010920:Placenta / Q000166:cytology / Q000378:metabolism*; D021041:Placental Circulation / Q000502:physiology; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism; D014327:Trophoblasts / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D011257:Pregnancy Proteins; C558404:Tpbpa protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C045073:Cre recombinase; D019426:Integrases
keywords: Cre-loxP; Flt1; Kdr; Prl3b1; VEGF-A; blood pressure; cardiac output; decidua; embryo loss; hypotension; junctional zone; labyrinth; placenta; placental circulation; placental hormones; placental lactogen; pregnancy; sFlt1; spongiotrophoblast; transgenic mice; vascular endothelial growth factor; vascular endothelial growth factor receptor-1; vascular endothelial growth factor receptor-2