Gessler and Lutz Hein

2-adrenoceptors are essential presynaptic regulators of norepinephrine release from sympathetic nerves. Previous studies in mice with targeted deletions in the 3 2-adrenoceptor genes have indicated that these receptors are essential for embryonic development. In the present study, we searched for the 2-adrenoceptor subtype(s) involved in placental development and its molecular mechanism using mice carrying targeted deletions in 2-adrenoceptor genes. Congenic 2B-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 upor downregulated 1.5-fold in 2B-deficient placentae. The type 1 receptor for vascular endothelial growth factor (Flt1), which is coexpressed with 2B-adrenoceptors in spongiotrophoblast and giant cells of the placenta, was found to be 2.3-fold upregulated in 2B-deficient placentae. Neutralization of Flt1 and its soluble splice variant sFlt1 by a specific antibody in vivo prevented the vascular defect in 2B-deficient placentae at embryonic day 10.5. Thus, 2B-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. (Circ Res. 2007;101:682-691.)