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1 Instiute for Medicine and Engineering, Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
2 Cell and Developmental Biology, University of Colorado Health Sciences Center, Aurora, Colorado, United States
3 Medicine, Vanderbilt University, Nashville, Tennessee, United States
4 Department of Medicine, University of Cambridge, Cambridge, United Kingdom
5 Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, Pennsylvania, United States
* To whom correspondence should be addressed. E-mail: jonespl{at}mail.med.upenn.edu.
Familial forms of human pulmonary arterial hypertension (FPAH) have been linked to mutations in BMP type II receptors (BMPR2s), yet the downstream targets of these receptors remain obscure. Herein, we show that pulmonary vascular lesions from patients harboring BMPR2 mutations express high levels of tenascin-C (TN-C), an extracellular matrix (ECM) 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. Further, Prx1 and TN-C promoter activities were significantly higher in FPAH versus normal SMCs. To delineate how BMPR2s control TN-C, we focused on R-Smads, downstream effectors activated by wild type BMPR2s. Nuclear localization and phosphorylation of R-Smads was greater in normal versus FPAH SMCs. As well, indirect blockade of R-Smad signaling using a kinase-deficient BMPRIb upregulated TN-C in normal SMCs. Since 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.
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