Upregulation of Soluble Vascular Endothelial Growth Factor Receptor 1 Contributes to Angiogenesis Defects in the Placenta of α2B-Adrenoceptor–Deficient Mice

• Published in: Circulation research 2007-09, Vol.101 (7), p.682-691
• Main Authors: Muthig, Verena, Gilsbach, Ralf, Haubold, Miriam, Philipp, Melanie, Ivacevic, Tomi, Gessler, Manfred, Hein, Lutz
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Fundamental and applied biological sciences. Psychology; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.107.151563

α2-adrenoceptors are essential presynaptic regulators of norepinephrine release from sympathetic nerves. Previous studies in mice with targeted deletions in the 3 α2-adrenoceptor genes have indicated that these receptors are essential for embryonic development. In the present study, we searched for the α2-adrenoceptor subtype(s) involved in placental development and its molecular mechanism using mice carrying targeted deletions in α2-adrenoceptor genes. Congenic α2B-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 α2B-deficient placentae. The type 1 receptor for vascular endothelial growth factor (Flt1), which is coexpressed with α2B-adrenoceptors in spongiotrophoblast and giant cells of the placenta, was found to be 2.3-fold upregulated in α2B-deficient placentae. Neutralization of Flt1 and its soluble splice variant sFlt1 by a specific antibody in vivo prevented the vascular defect in α2B-deficient placentae at embryonic day 10.5. Thus, α2B-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.