Upregulation of soluble vascular endothelial growth factor receptor 1 contributes to angiogenesis defects in the placenta of alpha 2B-adrenoceptor deficient mice

Circ Res. 2007 Sep 28;101(7):682-91. doi: 10.1161/CIRCRESAHA.107.151563. Epub 2007 Aug 2.


Alpha2-adrenoceptors are essential presynaptic regulators of norepinephrine release from sympathetic nerves. Previous studies in mice with targeted deletions in the 3 alpha2-adrenoceptor genes have indicated that these receptors are essential for embryonic development. In the present study, we searched for the alpha2-adrenoceptor subtype(s) involved in placental development and its molecular mechanism using mice carrying targeted deletions in alpha2-adrenoceptor genes. Congenic alpha2B-adrenoceptor-deficient mice (Adra2b-/-) developed a defect in fetal and maternal vessel formation in the placenta labyrinth at embryonic day 10.5. This defect was accompanied by reduced endothelial cell proliferation and decreased extracellular signal-regulated kinase 1/2 phosphorylation levels in Adra2b-/- as compared with Adra2b+/+ placentae. Microarray analysis of wild-type and mutant placentae (maternal genotype Adra2b+/-) revealed 179 genes, which were significantly up- or downregulated >1.5-fold in alpha2B-deficient placentae. The type 1 receptor for vascular endothelial growth factor (Flt1), which is coexpressed with alpha2B-adrenoceptors in spongiotrophoblast and giant cells of the placenta, was found to be 2.3-fold upregulated in alpha2B-deficient placentae. Neutralization of Flt1 and its soluble splice variant sFlt1 by a specific antibody in vivo prevented the vascular defect in alpha2B-deficient placentae at embryonic day 10.5. Thus, alpha2B-adrenoceptors are essential to suppress antiangiogenic (s)Flt1 in spongiotrophoblasts to control the coordinated formation of a vascular labyrinth of fetal and maternal blood vessels in the murine placenta during development.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neovascularization, Pathologic / metabolism*
  • Placenta / blood supply*
  • Placenta / metabolism*
  • Pregnancy
  • Receptors, Adrenergic, alpha-2 / deficiency*
  • Receptors, Adrenergic, alpha-2 / genetics
  • Receptors, Adrenergic, alpha-2 / metabolism*
  • Solubility
  • Up-Regulation / physiology*
  • Vascular Endothelial Growth Factor Receptor-1 / biosynthesis*
  • Vascular Endothelial Growth Factor Receptor-1 / genetics
  • Vascular Endothelial Growth Factor Receptor-1 / physiology


  • Adra2b protein, mouse
  • Receptors, Adrenergic, alpha-2
  • Vascular Endothelial Growth Factor Receptor-1