{Alpha}2B-adrenoceptor deficiency leads to postnatal respiratory failure in mice.
α(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 α(2)-adrenoceptors, the α(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 α(2B)-adrenoceptors are also involved in other developmental processes beyond placental angiogenesis. Ablation of α(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 α(2B)-deficient lungs and in isolated alveolar type II cells, expression of sonic hedgehog (SHH) was significantly increased, resulting in mesenchymal proliferation. In vitro α(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, α(2B)-adrenoceptors in lung epithelia play an important role in suppressing sonic hedgehog-mediated proliferation of mesenchymal cells and thus prevent respiratory failure.
Haubold
Miriam
M
Institute of Experimental and Clinical Pharmacology and Toxicology and the Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany.
Gilsbach
Ralf
R
Hein
Lutz
L
D000818:Animals; D019938:Cyclin D1 / Q000096:biosynthesis; D004195:Disease Models, Animal; D004848:Epithelium / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D006579:Heterozygote; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008171:Lung Diseases / Q000378:metabolism*; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018377:Neurotransmitter Agents / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000172:deficiency / Q000378:metabolism*; D014704:Veratrum Alkaloids / Q000494:pharmacology
C547772:Adra2b protein, mouse; D053823:Hedgehog Proteins; D019394:Ki-67 Antigen; D018377:Neurotransmitter Agents; D018341:Receptors, Adrenergic, alpha-2; D014704:Veratrum Alkaloids; D019938:Cyclin D1; C000541:cyclopamine