title: Endometrial VEGF induces placental sFLT1 and leads to pregnancy complications.
abstract: There is strong evidence that overproduction of soluble fms-like tyrosine kinase-1 (sFLT1) in the placenta is a major cause of vascular dysfunction in preeclampsia through sFLT1-dependent antagonism of VEGF. However, the cause of placental sFLT1 upregulation is not known. Here we demonstrated that in women with preeclampsia, sFLT1 is upregulated in placental trophoblasts, while VEGF is upregulated in adjacent maternal decidual cells. In response to VEGF, expression of sFlt1 mRNA, but not full-length Flt1 mRNA, increased in cultured murine trophoblast stem cells. We developed a method for transgene expression specifically in mouse endometrium and found that endometrial-specific VEGF overexpression induced placental sFLT1 production and elevated sFLT1 levels in maternal serum. This led to pregnancy losses, placental vascular defects, and preeclampsia-like symptoms, including hypertension, proteinuria, and glomerular endotheliosis in the mother. Knockdown of placental sFlt1 with a trophoblast-specific transgene caused placental vascular changes that were consistent with excess VEGF activity. Moreover, sFlt1 knockdown in VEGF-overexpressing animals enhanced symptoms produced by VEGF overexpression alone. These findings indicate that sFLT1 plays an essential role in maintaining vascular integrity in the placenta by sequestering excess maternal VEGF and suggest that a local increase in VEGF can trigger placental overexpression of sFLT1, potentially contributing to the development of preeclampsia and other pregnancy complications.
authors.forename: Xiujun
authors.initials: X
authors.lastname: Fan
authors.forename: Anshita
authors.initials: A
authors.lastname: Rai
authors.forename: Neeraja
authors.initials: N
authors.lastname: Kambham
authors.forename: Joyce F
authors.initials: JF
authors.lastname: Sung
authors.forename: Nirbhai
authors.initials: N
authors.lastname: Singh
authors.forename: Matthew
authors.initials: M
authors.lastname: Petitt
authors.forename: Sabita
authors.initials: S
authors.lastname: Dhal
authors.forename: Rani
authors.initials: R
authors.lastname: Agrawal
authors.forename: Richard E
authors.initials: RE
authors.lastname: Sutton
authors.forename: Maurice L
authors.initials: ML
authors.lastname: Druzin
authors.forename: Sanjiv S
authors.initials: SS
authors.lastname: Gambhir
authors.forename: Balamurali K
authors.initials: BK
authors.lastname: Ambati
authors.forename: James C
authors.initials: JC
authors.lastname: Cross
authors.forename: Nihar R
authors.initials: NR
authors.lastname: Nayak
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D004717:Endometrium / Q000201:enzymology*; D004790:Enzyme Induction; D005260:Female; D015870:Gene Expression; D008297:Male; D051379:Mice; D010920:Placenta / Q000201:enzymology*; D011225:Pre-Eclampsia / Q000201:enzymology*; D011247:Pregnancy; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1