title: A recently evolved novel trophoblast-enriched secreted form of fms-like tyrosine kinase-1 variant is up-regulated in hypoxia and preeclampsia.
abstract: BACKGROUND
  Recent published studies indicate a possible role for sFlt1 in the development of preeclampsia.
  
  
  OBJECTIVE
  The objective of the study was to investigate the expression and regulation of sFlt1-e15a, a recently described novel C-terminal variant isoform of sFlt1.
  
  
  METHODS
  The studies included a computational comparative analysis of the genomic locus of sFlt1 across vertebrate species; an assessment of sFlt1 variants in human and rhesus cells and tissues; an analysis of sFlt1 variants transiently expressed in HeLa and COS-7 cells; an evaluation of the effect of hypoxia on sFlt1 expression in trophoblasts; and a comparison of placental sFlt1 expression between pregnancies complicated by preeclampsia and control pregnancies.
  
  
  CONCLUSIONS
  sFlt1-e15a emerged as an alternate transcript of Flt1 late in evolution with the insertion of an AluSq sequence into the primate genome after the emergence of the simian infraorder about 40 million years ago. sFlt1-e15a is particularly abundant in human placenta and trophoblasts and is also highly expressed in nonhuman primate placenta. The expressed protein has a C-terminal polyserine tail and, like reference sequence sFlt1 (sFlt1-i13), is glycosylated and secreted. Consistent with a role in placental pathophysiology, hypoxia stimulates sFlt1-e15a expression in isolated cytotrophoblasts and a trophoblast cell line, and differentiation into syncytiotrophoblasts further enhances the effect of hypoxia. Placental levels of sFlt1-e15a and sFlt1-i13 transcripts are significantly elevated in patients with preeclampsia compared with normal pregnancies. We speculate that sFlt1-e15a may contribute to the pathophysiology of preeclampsia.
authors.affiliation: Department of Internal Medicine, of Iowa College of Medicine, Iowa City, Iowa 52242, USA. christie-thomas@uiowa.edu
authors.forename: Christie P
authors.initials: CP
authors.lastname: Thomas
authors.forename: Janet I
authors.initials: JI
authors.lastname: Andrews
authors.forename: Nandita S
authors.initials: NS
authors.lastname: Raikwar
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Kelley
authors.forename: Florian
authors.initials: F
authors.lastname: Herse
authors.forename: Ralf
authors.initials: R
authors.lastname: Dechend
authors.forename: Thaddeus G
authors.initials: TG
authors.lastname: Golos
authors.forename: Kang Z
authors.initials: KZ
authors.lastname: Liu