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Published ahead of print on September 10, 2004, doi:10.1164/rccm.200311-1602OC
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American Journal of Respiratory and Critical Care Medicine Vol 170. pp. 1340-1348, (2004)
© 2004 American Thoracic Society
doi: 10.1164/rccm.200311-1602OC

Original Article

Impaired Transforming Growth Factor-ß Signaling in Idiopathic Pulmonary Arterial Hypertension

Amy Richter, Michael E. Yeager, Ari Zaiman, Carlyne D. Cool, Norbert F. Voelkel and Rubin M. Tuder

Division of Cardiopulmonary Pathology, Department of Pathology, and Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and Graduate Program in Experimental Pathology, Department of Pathology, Pulmonary Hypertension Center, and Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Denver, Colorado

Correspondence and requests for reprints should be addressed to Rubin M. Tuder, M.D., Division of Cardiopulmonary Pathology, Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 519, Baltimore, MD 21205. E-mail: rtuder{at}jhmi.edu

Mutations in transforming growth factor-ß family receptor-II, bone morphogenetic protein receptor-2, and activin-like kinase-1 have been associated with pulmonary hypertension. In the present study, we determined that pulmonary arteries in normal lungs and in lungs of patients with emphysema and idiopathic pulmonary arterial hypertension comparably expressed transforming growth factor-ß receptors I and II, Smad(1, 5, 8), Smad2, Smad3, Smad4, phosphorylated Smad(1, 5, 8), and phosphorylated Smad2 (the latter two both indicative of active in vivo signaling) in endothelial cells, as assessed by immunohistochemistry and quantitative morphometry. Medial or intimal smooth muscle cells had weak or absent expression of these molecules. In clear contrast to endothelial cell expression in pulmonary arteries and in endothelial cells lining incipient vessels within plexiform lesions of hypertensive lungs, endothelial cells present in the core of the lesions lacked expression of all examined members of the signaling molecules. These findings were made irrespective of the mutation status of bone morphogenetic protein receptor-2 in hypertensive patients. Our findings suggest that pulmonary artery endothelial cells in both normal and severely hypertensive lungs have active transforming growth factor-ß family signaling, and that loss of signaling might contribute to the abnormal growth of endothelial cells in plexiform lesions in idiopathic pulmonary arterial hypertension.

Key Words: endothelial cells • pulmonary hypertension • Smad • smooth muscle cells • transforming growth factor-ß




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