␣ 2 -Adrenoceptors mediate diverse functions of the sympathetic system and are targets for the treatment of cardiovascular disease, depression, pain, glaucoma, and sympathetic activation during opioid withdrawal. To determine whether ␣ 2 -adrenoceptors on adrenergic neurons or ␣ 2 -adrenoceptors on nonadrenergic neurons mediate the physiological and pharmacological responses of ␣ 2 -agonists, we used the dopamine -hydroxylase (Dbh) promoter to drive expression of ␣ 2A -adrenoceptors exclusively in noradrenergic and adrenergic cells of transgenic mice. Dbh-␣ 2A transgenic mice were crossed with double knockout mice lacking both ␣ 2A -and ␣ 2C -receptors to generate lines with selective expression of ␣ 2A -autoreceptors in adrenergic cells. These mice were subjected to a comprehensive phenotype analysis and compared with wild-type mice, which express ␣ 2A -and ␣ 2C -receptors in both adrenergic and nonadrenergic cells, and ␣ 2A /␣ 2C double-knockout mice, which do not express these receptors in any cell type. We were surprised to find that only a few functions previously ascribed to ␣ 2 -adrenoceptors were mediated by receptors on adrenergic neurons, including feedback inhibition of norepinephrine release from sympathetic nerves and spontaneous locomotor activity. Other agonist effects, including analgesia, hypothermia, sedation, and anesthetic-sparing, were mediated by ␣ 2 -receptors in nonadrenergic cells. In dopamine -hydroxylase knockout mice lacking norepinephrine, the ␣ 2 -agonist medetomidine still induced a loss of the righting reflex, confirming that the sedative effect of ␣ 2 -adrenoceptor stimulation is not mediated via autoreceptor-mediated inhibition of norepinephrine release. The present study paves the way for a revision of the current view of the ␣ 2 -adrenergic receptors, and it provides important new considerations for future drug development.Adrenergic receptors are important targets for the treatment of human diseases and conditions including hypertension and heart failure, psychiatric and neurological diseases, asthma, and pain (Westfall and Westfall, 2006). To date, nine different adrenergic receptor subtypes have been cloned and grouped into three receptor groups, including ␣ 1A,B,D , ␣ 2A,B,C , and  1,2,3 (Bylund et al., 1994). However, the therapeutic potential of these subtypes has not been fully explored because of the lack of ligands with sufficient subtype-selectivity. At present, only four of the nine possible subtype distinctions (i.e., ␣ 1 , ␣ 2 ,  1 , and  2 ) have achieved clinical relevance (Westfall and Westfall, 2006). Especially within the ␣ 1 -and ␣ 2 -receptor subgroups, the physiological significance of individual receptor subtypes has remained unclear until recently. For the ␣ 2 -adrenoceptors, mouse models with targeted deletions of the individual subtypes have greatly advanced our understanding of the physiological role and the therapeutic potential of these receptors (Gilsbach and Hein, 2008). Activation of ␣ 2A -receptors could be linked with bradycardia ...
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.)
Background: Infantile hemangioma (Ih) is the most frequent vascular tumor of early childhood. Recently, propranolol, a nonselective β 1 -and β 2 -adrenoceptor inhibitor, was introduced into the therapy of severe proliferating Ih with excellent results. however, the underlying mechanism of action of propranolol is still unclear. Methods: We performed immunohistochemistry for cluster of differentiation 31 (cD31), D2-40, glucose transporter-1 (GLUT-1), and Ki67 in order to characterize 21 vascular anomalies (nine Ih, seven venous malformations (VMs), and five lymphatic malformations (LMs)). Furthermore, we analyzed the expression of β 1 -, β 2 -, and β 3 -adrenoceptor mRNA in these specimens as well as in hemangioma-derived stem cells by quantitative real-time PcR (qPcR). results: We show that the expression of β 1 -adrenoceptor mRNA is 10.7-fold higher in Ih independent of the proliferative or regressive phase as well as 2.5-fold higher in hemangioma-derived stem cells as compared with β 2 -adrenoceptor mRNA. In LM, the expression of β 2 -adrenoceptor mRNA was ninefold higher than that of β 1 -adrenoceptor mRNA. VM showed low expression levels of all β-adrenoceptor mRNAs, and β 3 -adrenoceptor mRNA was hardly detectable in any specimens examined. conclusion: These results provide the first evidence of distinctions between Ih and vascular malformations with regard to β-adrenoceptor subtype mRNA levels. r ecently, propranolol, a nonselective β-adrenoceptor inhibitor, was introduced into the therapy of severe proliferating infantile hemangioma (IH) (1). Propranolol treatment in IH results in fast growth inhibition and rapid tumor regression within a few days of therapy. This novel medical treatment has not been developed in a classic way; it was accidentally observed during corticosteroid therapy, the so far standard therapy for proliferating IH (2) when cardiac hypertrophy as a side effect is treated by propranolol. The molecular mechanism of propranolol on IH proliferation is unknown at present. A possible method of action could be vasoconstriction or induction of endothelial cell apoptosis (3). Inhibition of β-adrenoceptors has been suggested to have a negative impact on tumor development as well as a direct effect on endothelial cells by downregulation of angiogenesis factors such as vascular endothelial growth factor, matrix metalloproteinase-2, and matrix metalloproteinase-9 (4,5). A possible involvement of the β 2 -adrenoceptor/cyclic adenosine monophosphate pathway has been described in tumor vascularization of glioblastoma (4).IH is the most frequent benign tumor of early childhood that shows specific biological features: after an initial phase of proliferation during the first year of life, a long-lasting period of spontaneous regression over several years is observed (6). The underlying molecular mechanism could not be completely determined because of a lack of models for IH. Until recently, neither IH cell lines nor animal models were available. Endothelial cells from IH show specific expression of glucos...
␣ 2 -Adrenoceptors belong to the family of adrenergic receptors, which regulate the neuronal release of norepinephrine as part of a negative feedback loop. Among the ␣ 2 -adrenoceptors, the ␣ 2B -subtype may also influence developmental signaling pathways involved in angiogenesis of the placenta. Thus, the aim of the present study was to determine whether ␣ 2B -adrenoceptors are also involved in other developmental processes beyond placental angiogenesis. Ablation of ␣ 2B -adrenoceptors led to lethality of mutant mice during the first hours after birth. Despite normal breathing and drinking behavior, mutant mice developed cyanosis, which could be traced back to a defect in lung morphology with significantly reduced alveolar volume and thickened interalveolar septi. In ␣ 2B -deficient lungs and in isolated alveolar type II cells, expression of sonic hedgehog (SHH) was significantly increased, resulting in mesenchymal proliferation. In vitro ␣ 2B -adrenoreceptor stimulation suppressed expression of sonic hedgehog and the cell cycle genes cyclin D1 and Ki67. In vivo inhibition of enhanced SHH signaling by the smoothened antagonist cyclopamine partially rescued perinatal lethality, lung morphology, and altered gene expression in mutant mice. Thus, ␣ 2B -adrenoceptors in lung epithelia play an important role in suppressing sonic hedgehogmediated proliferation of mesenchymal cells and thus prevent respiratory failure.␣ 2 -Adrenoceptors belong to the family of G protein-coupled receptors that mediate the biological actions of the endogenous catecholamines noradrenaline and adrenaline (1, 2). These receptors were initially identified as presynaptic inhibitory feedback regulators of noradrenaline release from sympathetic or central adrenergic nerve terminals (3, 4). However, ␣ 2 -adrenoceptors have since also been found to mediate a wide spectrum of postsynaptic functions including hypotension and bradycardia, sedation, and analgesia (5-8). 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).Mice lacking functional ␣ 2A -, ␣ 2B -, and ␣ 2C -adrenoceptors on a mixed genetic background died between embryonic days 9.5 and 11.5 from a severe defect in yolk sac and placental development (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).The purpose of the present study was to identify the function of ␣ 2B -adrenoceptors in embryonic and perinatal development in mice. Here we demonstrate that ␣ 2B -deficient mice suffer from an early postnatal defect in lung maturation. In ␣ 2B -deficient lungs, sonic hedgehog (SHH) 2 and its receptor patched were up-regulated, resulting in enhanced mesenchymal proliferation. In vivo inhibition of SHH signaling by the smoothened antagonist cyclopamine partially rescued postnatal lethality and the pulmonary phenotype ass...
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