This Article Full Text Full Text (PDF) All Versions of this Article: 41/3/546    most recent 01.HYP.0000054213.37471.84v1 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 PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schauwienold, D. Articles by Reusch, H. P. Search for Related Content PubMed PubMed Citation Articles by Schauwienold, D. Articles by Reusch, H. P. Related Collections Cell signalling/signal transduction Gene expression Gene regulation Arrhythmias, clinical electrophysiology, drugs

(Hypertension. 2003;41:546.)
© 2003 American Heart Association, Inc.

Scientific Contributions

ERK1/2-Dependent Contractile Protein Expression in Vascular Smooth Muscle Cells

Dag Schauwienold; Claudia Plum; Thomas Helbing; Philipp Voigt; Thomas Bobbert; Dorett Hoffmann; Martin Paul; Hans Peter Reusch

From the Institut für Klinische Pharmakologie und Toxikologie, Freie Universität Berlin, Berlin, Germany.

Corresponding to H. Peter Reusch, Institut für Klinische Pharmakologie und Toxikologie, Freie Universität Berlin, Garystr. 5, 14195 Berlin, Germany. E-mail reusch{at}medizin.fu-berlin.de

In vivo, vascular smooth muscle (VSM) cells change their contractile phenotype toward a more proliferative phenotype during the pathogenesis of vascular diseases. Because these dedifferentiated VSM cells may gradually regain contractile functions, we aimed to identify signaling pathways that result in an increased expression of contractile proteins in VSM cells. In vitro, serum and thrombin induced a reversible upregulation of smooth muscle myosin heavy-chain (SM-MHC) in cultured neonatal rat VSM cells. Cotransfection of a SM-MHC–promoter chloramphenicol acetyltransferase–construct with dominant-negative N17Ras or N17Raf or treatment with the mitogen-activated/ERK-activating kinase (MEK) inhibitor PD 98059 concentration dependently decreased the serum- or thrombin-induced SM-MHC promoter activity. Consistently, the serum- or thrombin-induced phosphorylation of MEK and extracellular signal-regulated kinase 1/2 (ERK1/2) coincided with a MEK-dependent nuclear accumulation of phosphorylated ERK1/2 and subsequent nuclear phosphorylation of the transcription factors c-myc and Elk-1. A 5'-deletion analysis of cis-elements within the SM-MHC promoter demonstrated that a conserved region (nucleotide -1346 to -1102) was required for both cell type–specific expression and serum- or thrombin-induced upregulation of the SM-MHC promoter in VSM cells. Within this region, 2 CArG-boxes, a GC-rich element, and a CTF/NF-1 site are critical positively acting cis-elements for the serum- or thrombin-induced upregulation of SM-MHC. We conclude that the serum- or thrombin-induced differentiation requires an intact Ras/Raf/MEK/ERK signaling cascade, nuclear translocation of activated ERK1/2, phosphorylation of transcription factors, and several cis-elements within the SM-MHC promoter.

Key Words: atherosclerosis • contractile function • gene expression • phosphorylation • signal transduction

This article has been cited by other articles:

				P. J. Brighton, J. McDonald, A. H. Taylor, R. A. J. Challiss, D. G. Lambert, J. C. Konje, and J. M. Willets Characterization of Anandamide-Stimulated Cannabinoid Receptor Signaling in Human ULTR Myometrial Smooth Muscle Cells Mol. Endocrinol., September 1, 2009; 23(9): 1415 - 1427. [Abstract] [Full Text] [PDF]

				D. Schauwienold, A. P. Sastre, N. Genzel, M. Schaefer, and H. P. Reusch The Transactivated Epidermal Growth Factor Receptor Recruits Pyk2 to Regulate Src Kinase Activity J. Biol. Chem., October 10, 2008; 283(41): 27748 - 27756. [Abstract] [Full Text] [PDF]

				A. Perez Sastre, S. Grossmann, H. P. Reusch, and M. Schaefer Requirement of an Intermediate Gene Expression for Biphasic ERK1/2 Activation in Thrombin-stimulated Vascular Smooth Muscle Cells J. Biol. Chem., September 19, 2008; 283(38): 25871 - 25878. [Abstract] [Full Text] [PDF]

				E. Grantcharova, H. P. Reusch, S. Grossmann, J. Eichhorst, H.-W. Krell, M. Beyermann, W. Rosenthal, and A. Oksche N-Terminal Proteolysis of the Endothelin B Receptor Abolishes Its Ability to Induce EGF Receptor Transactivation and Contractile Protein Expression in Vascular Smooth Muscle Cells Arterioscler Thromb Vasc Biol, June 1, 2006; 26(6): 1288 - 1296. [Abstract] [Full Text] [PDF]

				J. P. Stegemann, H. Hong, and R. M. Nerem Mechanical, biochemical, and extracellular matrix effects on vascular smooth muscle cell phenotype J Appl Physiol, June 1, 2005; 98(6): 2321 - 2327. [Abstract] [Full Text] [PDF]

				T. Yoshida and G. K. Owens Molecular Determinants of Vascular Smooth Muscle Cell Diversity Circ. Res., February 18, 2005; 96(3): 280 - 291. [Abstract] [Full Text] [PDF]

				K. A. Martin, E. M. Rzucidlo, B. L. Merenick, D. C. Fingar, D. J. Brown, R. J. Wagner, and R. J. Powell The mTOR/p70 S6K1 pathway regulates vascular smooth muscle cell differentiation Am J Physiol Cell Physiol, March 1, 2004; 286(3): C507 - C517. [Abstract] [Full Text]

				G.-X. Zhang, S. Kimura, A. Nishiyama, T. Shokoji, M. Rahman, and Y. Abe ROS During the Acute Phase of Ang II Hypertension Participates in Cardiovascular MAPK Activation But Not Vasoconstriction Hypertension, January 1, 2004; 43(1): 117 - 124. [Abstract] [Full Text] [PDF]