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(Circulation. 2004;110:3245-3251.)
© 2004 American Heart Association, Inc.

Molecular Cardiology

Pulmonary Hypertension and Right Heart Failure in Pituitary Adenylate Cyclase–Activating Polypeptide Type I Receptor–Deficient Mice

Christiane Otto, MD, PhD; Lutz Hein, MD; Marc Brede, MD; Roland Jahns, MD; Stefan Engelhardt, MD, PhD; Hermann-Josef Gröne, MD; Günther Schütz, MD

From Division of Molecular Biology of the Cell (C.O., G.S.), German Cancer Research Center, Heidelberg; the Institute of Pharmacology (L.H., M.B., R.J., S.E.), University of Würzburg, Würzburg; and the Department of Cellular and Molecular Pathology (H.-J.G.), German Cancer Research Center, Heidelberg, Germany.

Correspondence to Günther Schütz, Molecular Biology of the Cell, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. E-mail g.schuetz{at}dkfz-heidelberg.de

Received October 22, 2003; de novo received April 20, 2004; revision received June 22, 2004; accepted June 23, 2004.

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.

Methods and 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.

Key Words: hypertension, pulmonary • heart failure • genetics

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