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Published ahead of print on September 10, 2004, doi:10.1164/rccm.200311-1602OC

Am. J. Respir. Crit. Care Med., Volume 170, Number 12, December 2004, 1340-1348

A more recent version of this article appeared on December 15, 2004
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Submitted on November 25, 2003
Accepted on September 7, 2004

Impaired Transforming Growth Factor--{beta} Signaling in Idiopathic Pulmonary Arterial Hypertension

Amy Richter1, Michael E Yeager2, Ari Zaiman3, Carlyne D Cool4, Norbert F Voelkel5, and Rubin M Tuder6*

1 Division of Cardiopulmonary Pathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA, 2 Division of Cardiopulmonary Pathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Graduate Program in Experimental Pathology, University of Colorado School of Medicine, Denver, CO, USA, 3 Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA, 4 Department of Pathology, University of Colorado School of Medicine, Denver, CO, USA; Pulmonary Hypertension Center, University of Colorado School of Medicine, Denver, CO, USA, 5 Pulmonary Hypertension Center, University of Colorado School of Medicine, Denver, CO, USA; Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Denver, CO, USA, 6 Division of Cardiopulmonary Pathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

* To whom correspondence should be addressed. E-mail: rtuder{at}jhmi.edu.

Mutations in transforming growth factor-{beta} family receptor-II, bone morphogenetic protein receptor-2 and Activin-like kinase1 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-{beta} receptors I and II, Smad(1,5, or 8), Smad2, Smad3, Smad4, phosphorylated Smad(1,5, or 8) and phosphorylated Smad2 (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 irrespective of the mutation status in the 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-{beta} 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: TGF-beta, pulmonary hypertension, endothelial cells, Smad, smooth muscle cells




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