Tenascin-C is induced by mutated BMP type II receptors in familial forms of pulmonary arterial hypertension

• Published in: American journal of physiology. Lung cellular and molecular physiology 2006-10, Vol.291 (4), p.L694-L702
• Main Authors: Ihida-Stansbury, Kaori, McKean, David M, Lane, Kirk B, Loyd, James E, Wheeler, Lisa A, Morrell, Nicholas W, Jones, Peter Lloyd
• Format: Article
• Language: English
• Subjects: Bone Morphogenetic Protein Receptors - antagonists & inhibitors; Bone Morphogenetic Protein Receptors, Type II - genetics; Bone Morphogenetic Protein Receptors, Type II - metabolism; Cells, Cultured; Extracellular Signal-Regulated MAP Kinases - metabolism; Homeodomain Proteins - metabolism; Humans; Hypertension, Pulmonary - genetics; Hypertension, Pulmonary - metabolism; Mutation; Myocytes, Smooth Muscle - metabolism; Pulmonary Artery - metabolism; Pulmonary Artery - pathology; Signal Transduction; Smad Proteins, Receptor-Regulated - metabolism; Tenascin - biosynthesis
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00119.2006

1 Institute for Medicine and Engineering and 2 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; 3 Department of Cell and Developmental Biology, University of Colorado Health Sciences Center, Denver, Colorado; 4 Department of Medicine, Vanderbilt University, Nashville, Tennessee; and 5 Department of Medicine, University of Cambridge, Cambridge, United Kingdom Submitted 31 March 2006 ; accepted in final form 13 May 2006 Familial forms of human pulmonary arterial hypertension (FPAH) have been linked to mutations in bone morphogenetic protein (BMP) type II receptors (BMPR2s), yet the downstream targets of these receptors remain obscure. Here we show that pulmonary vascular lesions from patients harboring BMPR2 mutations express high levels of tenascin-C (TN-C), an extracellular matrix glycoprotein that promotes pulmonary artery (PA) smooth muscle cell (SMC) proliferation. To begin to define how TN-C is regulated, PA SMCs were cultured from normal subjects and from those with FPAH due to BMPR2 mutations. FPAH SMCs expressed higher levels of TN-C than normal SMCs. Similarly, expression of Prx1, a factor that drives TN-C transcription, was elevated in FPAH vascular lesions and SMCs derived thereof. Furthermore, Prx1 and TN-C promoter activities were significantly higher in FPAH vs. normal SMCs. To delineate how BMPR2s control TN-C, we focused on receptor (R)-Smads, downstream effectors activated by wild-type BMPR2s. Nuclear localization and phosphorylation of R-Smads was greater in normal vs. FPAH SMCs. As well, indirect blockade of R-Smad signaling with a kinase-deficient BMP receptor Ib upregulated TN-C in normal SMCs. Because ERK1/2 MAPKs inhibit the transcriptional activity of R-Smads, and because ERK1/2 promotes TN-C transcription, we determined whether ERK1/2 inhibits R-Smad signaling in FPAH SMCs and whether this activity is required for TN-C transcription. Indeed, ERK1/2 activity was greater in FPAH SMCs, and inhibition of ERK1/2 resulted in nuclear localization of R-Smads and inhibition of TN-C. These studies define a novel signaling network relevant to PAH underscored by BMPR2 mutations. pulmonary hypertension; bone morphogenetic protein receptors; extracellular matrix Address for reprint requests and other correspondence: P. L. Jones, Univ. of Pennsylvania, Inst. for Medicine & Engineering, 1010 Vagelos Research Laboratories, 3340 Smith Walk, Philadelphia, PA 19104-6383 (e-mail: jonespl{at}mail.me