Upregulation of soluble vascular endothelial growth factor receptor 1 contributes to angiogenesis defects in the placenta of alpha 2B-adrenoceptor deficient mice.
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.
Institute of Experimental and Clinical Pharmacology, University of Freiburg, Albertstrasse 25, 79104 Freiburg, Germany.
Verena
V
Muthig
Ralf
R
Gilsbach
Miriam
M
Haubold
Melanie
M
Philipp
Tomi
T
Ivacevic
Manfred
M
Gessler
Lutz
L
Hein
D000818:Animals; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010920:Placenta / Q000098:blood supply* / Q000378:metabolism*; D011247:Pregnancy; D018341:Receptors, Adrenergic, alpha-2 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D012995:Solubility; D015854:Up-Regulation / Q000502:physiology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology
C547772:Adra2b protein, mouse; D018341:Receptors, Adrenergic, alpha-2; D040281:Vascular Endothelial Growth Factor Receptor-1