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(Circulation Research. 2007;101:682.)
© 2007 American Heart Association, Inc.

Molecular Medicine

Upregulation of Soluble Vascular Endothelial Growth Factor Receptor 1 Contributes to Angiogenesis Defects in the Placenta of _2B-Adrenoceptor–Deficient Mice

Verena Muthig, Ralf Gilsbach, Miriam Haubold, Melanie Philipp, Tomi Ivacevic, Manfred Gessler, Lutz Hein

From the Institute of Experimental and Clinical Pharmacology (V.M., R.G., M.H., M.P., L.H.), University of Freiburg, Germany; Institute of Cell Biology (M.P.), Duke University Medical Center, Durham, NC; European Molecular Biology Laboratory (T.I.), Heidelberg, Germany; and Department of Physiological Chemistry (M.G.), Biocenter, University of Würzburg, Germany.

Correspondence to Lutz Hein, MD, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Albertstrasse 25, 79104 Freiburg, Germany. E-mail lutz.hein{at}pharmakol.uni-freiburg.de

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 up- or 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.

Key Words: adrenergic receptors • angiogenesis • gene-targeted mice • vascular endothelial growth factor

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