Published online before print July 5, 2001, doi: 10.1161/hh1401.093582
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© 2001 American Heart Association, Inc.
Molecular Medicine |
Prx1 Controls Vascular Smooth Muscle Cell Proliferation and Tenascin-C Expression and Is Upregulated With Prx2 in Pulmonary Vascular Disease
From the Department of Neurobiology (F.R.J., R.M.), Scripps Research Institute, La Jolla, and The Neurosciences Institute (D.B.E.), San Diego, Calif; Children’s Hospital of Philadelphia and Department of Pediatrics (R.J.O., P.L.J.), University of Pennsylvania School of Medicine, Philadelphia, Penn; and Department of Pediatrics (P.L.J.), Section of Critical Care, University of Colorado Health Sciences Center, Denver, Colo.
Correspondence to Peter Lloyd Jones, PhD, University of Colorado Health Sciences Center, 4200 East Ninth Ave, B-131, Denver, CO 80242. E-mail peter.jones{at}uchsc.edu
Abstract— Prx1 and Prx2 are homeobox transcription factors expressed during vasculogenesis. To begin to elucidate how Prx1 and Prx2 are regulated and function in the adult vasculature, in situ hybridization studies were performed. Prx1 and Prx2 mRNAs were not detected in normal adult rat pulmonary arteries; however, both genes were induced with vascular disease, colocalizing to sites of tenascin-C (TN-C) expression. Because catabolism of the extracellular matrix (ECM) is a critical step in the development of vascular disease, we investigated whether changes in vascular smooth muscle cell (SMC)–ECM interactions regulate Prx1 and Prx2. A10 SMCs cultured on native type I collagen showed low levels of Prx1 and Prx2 mRNA expression, whereas cells cultured on denatured collagen showed higher levels of expression of both genes. At a functional level, transfection of SMCs with a Prx1 expression plasmid significantly increased their growth. Because TN-C also promotes SMC growth and its expression is also upregulated by denatured collagen, we tested and thereafter showed that Prx1 expression significantly enhances TN-C gene promoter activity 20-fold. Similar experiments conducted with truncated Prx1 proteins showed that the N-terminal portion and the homeodomain of Prx1 were necessary to induce the bulk of TN-C promoter activity. These findings support the hypothesis that Prx genes are regulated by changes in SMC adhesion and play key morphoregulatory roles during the development and progression of pulmonary vascular disease in adults.
Key Words: tenascin-C • homeobox genes • pulmonary
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