title: Tenascin-C is induced by mutated BMP type II receptors in familial forms of pulmonary arterial hypertension.
abstract: 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.
authors.affiliation: University of Pennsylvania, Institute for Medicine & Engineering, Department of Pathology and Laboratory Medicine, Philadelphia, PA 19104-6383, USA.
authors.forename: Kaori
authors.initials: K
authors.lastname: Ihida-Stansbury
authors.forename: David M
authors.initials: DM
authors.lastname: McKean
authors.forename: Kirk B
authors.initials: KB
authors.lastname: Lane
authors.forename: James E
authors.initials: JE
authors.lastname: Loyd
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Wheeler
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
authors.forename: Peter Lloyd
authors.initials: PL
authors.lastname: Jones
mesh_terms: D052004:Bone Morphogenetic Protein Receptors / Q000037:antagonists & inhibitors; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D051896:Smad Proteins, Receptor-Regulated / Q000378:metabolism; D019063:Tenascin / Q000096:biosynthesis
chemical_list: D018398:Homeodomain Proteins; C082157:PRRX1 protein, human; D051896:Smad Proteins, Receptor-Regulated; D019063:Tenascin; D048049:Extracellular Signal-Regulated MAP Kinases; D052004:Bone Morphogenetic Protein Receptors; D052006:Bone Morphogenetic Protein Receptors, Type II