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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1072.)
© 2007 American Heart Association, Inc.

Vascular Biology

Dysregulated Bone Morphogenetic Protein Signaling in Monocrotaline-Induced Pulmonary Arterial Hypertension

Rory E. Morty; Bozena Nejman; Grazyna Kwapiszewska; Matthias Hecker; Anka Zakrzewicz; Fotini M. Kouri; Dorothea M. Peters; Rio Dumitrascu; Werner Seeger; Petra Knaus; Ralph T. Schermuly; Oliver Eickelberg

From the Department of Internal Medicine (R.M., B.N., G.K., M.H., A.Z., F.K., D.P., R.D., W.S., R.S., O.E.), University of Giessen Lung Center, Justus Liebig University, Giessen; and the Institute of Chemistry and Biochemistry (P.K.), Free University of Berlin, Germany.

Correspondence to Rory E. Morty, Department of Internal Medicine, University of Giessen Lung Center, Justus Liebig University, Aulweg 123 (Raum 6-11), D-35392 Giessen, Germany. E-mail rory.morty{at}innere.med.uni-giessen.de

Background— Mutations in the bmpr2 gene, encoding the type II bone morphogenetic protein (BMP) receptor, have been identified in patients with pulmonary arterial hypertension (PAH), implicating BMP signaling in PAH. The aim of this study was to assess BMP signaling and its physiological effects in a monocrotaline (MCT) model of PAH.

Methods and Results— Expression of BMP receptors Ib and II, and Smads 4, 5, 6, and 8, was downregulated in lungs but not kidneys of MCT-treated rats. Smad1 phosphorylation and expression of BMP/Smad target genes id1 and id3 was also reduced, although ERK1/2 and p38^MAPK phosphorylation remained unaffected. BMP receptor and Smad expression, Smad1 phosphorylation, and induction of the BMP/Smad-responsive element of the id1 promoter were reduced in pulmonary artery smooth muscle cells (PASMCs) from MCT-treated rats. As a consequence of impaired BMP/Smad signaling, PASMCs from MCT-treated rats were resistant to apoptosis induced by BMP-4 and BMP-7, and were also resistant to BMP-4 antagonism of proliferation induced by platelet-derived growth factor.

Conclusion— BMP signaling and BMP-regulated physiological phenomena are perturbed in MCT-treated rats, lending solid support to the proposed roles for BMP signaling in the pathogenesis of human PAH.

The expression and function of the BMP/Smad signaling axis is perturbed in monocrotaline-induced pulmonary arterial hypertension in rats, whereas MAP kinase signaling appears unaffected. These data support a role for dysregulated BMP/Smad signaling in the pathogenesis of pulmonary arterial hypertension.

Key Words: bone morphogenetic proteins • monocrotaline • pulmonary arterial hypertension • Smad • vascular remodeling • VSMC proliferation

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