Abstract 431: Upregulation of Soluble VEGF Receptor 1 Contributes to Angiogenesis Defects in the Placenta of alpha2B-Adrenoceptor Deficient Mice
α2-adrenoceptors are essential presynaptic regulators of norepinephrine release from sympathetic nerves. Previous studies in mice with targeted deletions in the three α2-adrenoceptor genes have indicated that these receptors are essential for embryonic development by regulating the formation of blood vessels in extraembryonic tissues. 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 developed a defect in fetal and maternal vessel formation in the placenta labyrinth at embryonic day E10.5. This defect was accompanied by reduced endothelial cell proliferation and decreased ERK1/2 phosphorylation levels in α2B−/−as compared with α2B+/+ placenta. Placenta development and structure was not affected by deletion of the α2A- or α2C-adrenoceptor subtypes. Microarray analysis of wild-type and mutant placentae (maternal genotype α2B+/−) revealed 179 genes which were significantly up- or downregulated >1.5-fold in α2B-deficient placenta. 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 placenta. Furthermore, α2B-receptor deletion resulted in upregulation of the soluble splice variant sFlt-1 (sVEGFR-1). Neutralization of Flt1 and its soluble splice variant sFlt1 by a specific antibody in vivo prevented the vascular defect in α2B-deficient placenta at E10.5. In to investigate whether the effects of α2B-adrenoceptors are restricted to vascular development in the placenta, capillary density was investigated in a hindlimb model of ischemia. Occlusion of the femoral artery for 14 days resulted in a decreased capillary density in the occluded limbs of α2B−/− mice as compared with α2B+/+ mice. Thus, α2B-adrenoceptors are essential to suppress antiangiogenic (s)Flt1 to control the coordinated formation of a vascular labyrinth of fetal and maternal blood vessels in the murine placenta during development. In addition, α2B-receptors modulate angiogenesis in the adult organism.