title: Pulmonary hypertension and right heart failure in pituitary adenylate cyclase-activating polypeptide type I receptor-deficient mice.
abstract: BACKGROUND
  Pituitary adenylate cyclase-activating polypeptide (PACAP), acting via 3 different G protein-coupled receptors, has been implicated in the regulation of several homeostatic systems in the body, including cardiopulmonary control. To define the physiologic role of the PACAP-preferring type I receptor, PAC1, in cardiopulmonary function, we developed a mutant mouse strain lacking functional PAC1 receptors.
  
  
  RESULTS
  When PAC1-deficient mice were crossed onto a C57BL/6 background, almost all mutants died during the second postnatal week. Whereas mutant mice were indistinguishable from their wild-type littermates at birth, they showed progressive weakness and died from rapidly developing heart failure. Right ventricles of PAC1 mutants were massively dilated and showed cardiac myocyte hypertrophy, whereas left ventricular structure was unaltered. On direct cardiac catheterization, right ventricular pressure was elevated by 45% in PAC1-deficient mice, indicating increased pulmonary artery pressure, as no malformations were detected in the valves or outflow tract of the right ventricle. Consistent with elevated pulmonary pressure, lung capillary density was decreased by 30% and small pulmonary arteries of mutant mice had significant vascular smooth muscle cell hypertrophy compared with wild-type mice.
  
  
  CONCLUSIONS
  Whereas PACAP induces vasodilation in isolated pulmonary vessels in wild-type mice, the absence of its specific receptor PAC1 causes pulmonary hypertension and right heart failure after birth. These in vivo findings demonstrate the crucial importance of PAC1-mediated signaling for the maintenance of normal pulmonary vascular tone during early postnatal life.
authors.affiliation: Division of Molecular Biology of the Cell, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Otto
authors.forename: Lutz
authors.initials: L
authors.lastname: Hein
authors.forename: Marc
authors.initials: M
authors.lastname: Brede
authors.forename: Roland
authors.initials: R
authors.lastname: Jahns
authors.forename: Stefan
authors.initials: S
authors.lastname: Engelhardt
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.forename: Günther
authors.initials: G
authors.lastname: Schütz
mesh_terms: D000818:Animals; D002196:Capillaries / Q000473:pathology; D048429:Cell Size; D003345:Corticosterone / Q000097:blood; D003433:Crosses, Genetic; D006333:Heart Failure / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000378:metabolism; D006984:Hypertrophy; D017380:Hypertrophy, Right Ventricular / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D008168:Lung / Q000098:blood supply; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology; D009414:Nerve Growth Factors / Q000502:physiology*; D009479:Neuropeptides / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000502:physiology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011312:Pressure; D011651:Pulmonary Artery / Q000254:growth & development / Q000473:pathology; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D015398:Signal Transduction; D014463:Ultrasonography; D014655:Vascular Resistance / Q000502:physiology*; D014664:Vasodilation / Q000235:genetics / Q000502:physiology
chemical_list: C495402:Adcyap1 protein, mouse; C495504:Adcyap1r1 protein, mouse; D009414:Nerve Growth Factors; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011956:Receptors, Cell Surface; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D003345:Corticosterone