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

Abstract

Abstract-␣ 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 Ϫ/Ϫ ) 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 Ϫ/Ϫ as compared with Adra2bplacentae. Microarray analysis of wild-type and mutant placentae (maternal genotype Adra2b ϩ/Ϫ ) revealed 179 genes, which were significantly up-or downregulated Ͼ1.5-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.)

α2B-Adrenoceptor Deficiency Leads to Postnatal Respiratory Failure in Mice*

“…In addition, the ␣ 2B -subtype is unique among the adrenoceptors because it plays an essential role during embryonic development (9,10). Although previous studies have demonstrated the involvement of ␣ 2B -receptors in extraembryonic development (9, 10), i.e.…”

“…For this study, Adra2b Ϫ/Ϫ mice, which were backcrossed onto a C57BL/6 background (Harlan Winkelmann, Borchen, Germany) for 12 generations, were used (9). All animal procedures were approved by the responsible animal care committee of the University of Freiburg, Germany.…”

“…All animal procedures were approved by the responsible animal care committee of the University of Freiburg, Germany. Genotyping was performed with primers as described previously (9). Cyclopamine (18 mg/kg of body weight, SigmaAldrich, Taufkirchen, Germany) was applied subcutaneously to pregnant mice.…”

“…However, ␣ 2 -adrenoceptors have since also been found to mediate a wide spectrum of postsynaptic functions including hypotension and bradycardia, sedation, and analgesia (5)(6)(7)(8). In addition to the modulation of physiological functions in the adult organism, the ␣ 2B -receptor subtype also plays an important role during embryonic development (9,10).…”

“…This defect was mostly ascribed to loss of ␣ 2B -adrenoreceptor function as ␣ 2B -deficient mice, which were backcrossed onto a C57BL/6 background, showed a similar defect in placenta vasculogenesis (9).…”