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

Abstract

␣ 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...

Are the pharmacology and physiology of α2adrenoceptors determined by α2‐heteroreceptors and autoreceptors respectively?

“…While such substances have recently become available (Crassous et al ., 2007a; Gentili et al ., 2007; Sallinen et al ., 2007) studies in mice with ablation of the individual α 2 ‐subtypes clearly show that only a few functions rely on a single subtype. For example, α 2B ‐adrenoceptors play an important role in development of the placenta (Philipp et al ., 2002; Muthig et al ., 2007) and the lung (Haubold et al ., 2010) and they regulate vascular tone (Link et al ., 1996). α 2C ‐Adrenoceptors were identified as the major feedback receptors of adrenaline release from chromaffin cells in the adrenal medulla (Brede et al ., 2002; 2003; Gilsbach et al ., 2007).…”

Evolution of the α2-adrenoreceptors in vertebrates: ADRA2D is absent in mammals and crocodiles

“…CC-BY-NC-ND 4.0 International license a certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under The copyright holder for this preprint (which was not this version posted February 7, 2017. ; https://doi.org/10.1101/106526 doi: bioRxiv preprint 1996) as well as in the development of the placenta (Muthig et al, 2007) and lungs (Haubold et al, 2010). The α 2C -adrenoreceptors (ADRA2C) control the secretion of epinephrine via an autocrine feedback loop in the adrenal medulla (Brede et al, 2002(Brede et al, , 2003Gilsbach et al, 2007).…”

Evolution of the α2-adrenoreceptors in vertebrates: ADRA2D is absent in mammals and crocodiles

“…At the individual level, the α 2A -adrenoreceptors (ADRA2A) mediate inhibition of insulin release (Gribble, 2010;Rosengren et al, 2010), hypotension, bradycardia, baroreceptor reflex sensitivity, sedation, and hypnosis (MacMillan et al, 1996;Lakhlani et al, 1997, Niederhoffer et al, 2004. The α 2B -adrenoreceptors (ADRA2B) play important roles in the regulation of vascular tone (Link et al, 1996) as well as in the development of the placenta and lungs (Haubold et al, 2010). The α 2C -adrenoreceptors (ADRA2C) control the secretion of epinephrine via an autocrine feedback loop in the adrenal medulla (Brede et al, , 2003Gilsbach et al, 2007).…”