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This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 296/2/H442    most recent 00165.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Thomas, J. A. Articles by Owens, G. K. Search for Related Content PubMed PubMed Citation Articles by Thomas, J. A. Articles by Owens, G. K.

PDGF-DD, a novel mediator of smooth muscle cell phenotypic modulation, is upregulated in endothelial cells exposed to atherosclerosis-prone flow patterns

Departments of ¹Molecular Physiology and Biological Physics, ²Biomedical Engineering, and ³Cardiovascular Medicine and ⁴Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia; ⁵Ludwig Institute for Cancer Research, Stockholm Branch, Stockholm, Sweden; ⁶Department of Hematology/Oncology, ZymoGenetics, Seattle, Washington; and ⁷Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, Greece

Submitted 16 February 2008 ; accepted in final form 20 November 2008

Platelet-derived growth factor (PDGF)-BB is a well-known smooth muscle (SM) cell (SMC) phenotypic modulator that signals by binding to PDGF -, β-, and ββ-membrane receptors. PDGF-DD is a recently identified PDGF family member, and its role in SMC phenotypic modulation is unknown. Here we demonstrate that PDGF-DD inhibited expression of multiple SMC genes, including SM -actin and SM myosin heavy chain, and upregulated expression of the potent SMC differentiation repressor gene Kruppel-like factor-4 at the mRNA and protein levels. On the basis of the results of promoter-reporter assays, changes in SMC gene expression were mediated, at least in part, at the level of transcription. Attenuation of the SMC phenotypic modulatory activity of PDGF-DD by pharmacological inhibitors of ERK phosphorylation and by a small interfering RNA to Kruppel-like factor-4 highlight the role of these two pathways in this process. PDGF-DD failed to repress SM -actin and SM myosin heavy chain in mouse SMCs lacking a functional PDGF β-receptor. Importantly, PDGF-DD expression was increased in neointimal lesions in the aortic arch region of apolipoprotein C-deficient (ApoE^–/–) mice. Furthermore, human endothelial cells exposed to an atherosclerosis-prone flow pattern, as in vascular regions susceptible to the development of atherosclerosis, exhibited a significant increase in PDGF-DD expression. These findings demonstrate a novel activity for PDGF-DD in SMC biology and highlight the potential contribution of this molecule to SMC phenotypic modulation in the setting of disturbed blood flow.

shear stress; disturbed blood flow; smooth muscle myosin heavy chain; smooth muscle -actin