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Published ahead of print on November 21, 2008, doi:10.1165/rcmb.2008-0153OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 40, pp. 683-691, 2009
© 2009 American Thoracic Society
DOI: 10.1165/rcmb.2008-0153OC

The Noncanonical WNT Pathway Is Operative in Idiopathic Pulmonary Arterial Hypertension

Isabel P. Laumanns1,3, Ludger Fink2, Jochen Wilhelm2, Jens-C. Wolff1,3, Rita Mitnacht-Kraus1, Sabine Graef-Hoechst1, Maria M. Stein2, Rainer M. Bohle5, Walter Klepetko4, Mir A. R. Hoda4, Ralph T. Schermuly1,3, Friedrich Grimminger1, Werner Seeger1,3 and Robert Voswinckel1,3

1 Department of Internal Medicine, and 2 Institute of Pathology, University Hospital of Giessen, Giessen, Germany; 3 Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany; 4 Department of Cardiothoracic Surgery, University of Vienna, Vienna, Austria; and 5 Department of Pathology, University of the Saarland, Homburg/Saar, Germany

Correspondence and requests for reprints should be addressed to Robert Voswinckel, M.D., University Hospital Giessen and Marburg GmbH, Department of Internal Medicine, Klinikstrasse 36, D-35392 Giessen, Germany. E-mail: robert.voswinckel{at}innere.med.uni-giessen.de

Idiopathic pulmonary arterial hypertension (IPAH) is a fatal disease that comprises sustained vasoconstriction, enhanced proliferation of pulmonary vascular cells, and in situ thrombosis. The discovery of several contributing signaling pathways in recent years has resulted in an expanding array of novel therapies; however, IPAH remains a progressive disease with poor outcome in most instances. To identify new regulatory pathways of vascular remodeling in IPAH, we performed transcriptome-wide expression profiling of laser-microdissected pulmonary arterial resistance vessels derived from explanted IPAH and nontransplanted donor lung tissues. Statistical analysis of the data derived from six individuals in each group showed significant regulation of several mediators of the canonical and noncanonical WNT pathway. As to the noncanonical WNT pathway, the planar cell polarity (PCP) pathway, the ras homolog gene family member A (RHOA), and ras-related C3 botulinum toxin substrate-1 (RAC1) were strongly up-regulated. Real-time PCR of laser-microdissected pulmonary arteries confirmed these array results and showed in addition significant up-regulation of further PCP mediators wingless member 11 (WNT11), disheveled associated activator of morphogenesis-1 (DAAM1), disheveled (DSV), and RHO-kinase (ROCK). Immunohistochemical staining and semiquantitative expression analysis confirmed the markedly enhanced expression of the PCP mediators in the pulmonary resistance vessels, in particular in the endothelial layer in IPAH. Therefore we propose the PCP pathway to be critically involved in the regulation of vascular remodeling in IPAH.

Key Words: planar cell polarity • molecular medicine • vascular remodeling • pulmonary resistance arteries • laser-microdissection


CLINICAL RELEVANCE

This is the first compartment-specific analysis of idiopathic pulmonary arterial hypertension (IPAH) arteries. Interesting new candidates were revealed. The WNT signaling pathway was identified in the pathogenesis of IPAH and might be a potential new therapeutic approach.

 



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