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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1288.)
© 2006 American Heart Association, Inc.

Vascular Biology

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

Evelina Grantcharova; H. Peter Reusch; Solveig Grossmann; Jenny Eichhorst; Hans-Willi Krell; Michael Beyermann; Walter Rosenthal; Alexander Oksche

From the Institut für Pharmakologie (E.G., S.G., W.R., A.O.), Charité Campus Benjamin Franklin, Berlin, Germany; Leibniz-Institut für Molekulare Pharmakologie (E.G., J.E., M.B., W.R., A.O.), Campus Berlin-Buch, Berlin, Germany; Abteilung für Klinische Pharmakologie (H.P.R.), Ruhr-Universität Bochum, Germany; and Roche-Diagnostics GmbH (H.-W.K.), Pharma-Research Penzberg, Germany.

Correspondence to Alexander Oksche, Institut für Pharmakologie, Charité Campus Benjamin Franklin, Thielallee 67-73, 14195 Berlin, Germany. E-mail oksche{at}arcor.de

Objective— The extracellular N terminus of the endothelin B (ET_B) receptor is cleaved by a metalloprotease in an agonist-dependent manner, but the physiological role of this N-terminal proteolysis is not known. In this study, we aimed to determine the functional role of the ET_B receptor and of its N-terminal cleavage in vascular smooth muscle cells (VSMCs).

Methods and Results— VSMCs expressing either the full-length ET_B receptor or an N-terminally truncated ET_B receptor (corresponding to the N-terminally cleaved receptor) were analyzed for ligand-induced mitogen-activated protein kinase activation and expression of contractile proteins. In VSMCs expressing the full-length ET_B receptor, IRL1620 (an ET_B-selective agonist) induced a biphasic extracellular signal-regulated kinase 1/2 (ERK1/2) activation and increased expression of contractile proteins (smooth muscle myosin-1 [SM-1]/SM-2, SM22, and -actin). Interestingly, the second phase of ERK1/2 activation required metalloprotease activity, epidermal growth factor (EGF) receptor transactivation, and predominantly activation of G_i proteins. In contrast, in VSMCs expressing N-terminally truncated ET_B receptors, IRL1620 did not elicit EGF transactivation and failed to increase contractile protein expression.

Conclusions— This study is the first to show that stimulation of full-length ET_B receptors promotes expression of contractile proteins and may thus participate in the differentiation of VSMCs.

The ET_B receptor undergoes agonist-induced N-terminal proteolysis. Postreceptor signaling comprised biphasic ERK1/2 activation, EGF receptor transactivation, and an increased expression of contractile proteins in vascular smooth muscle cells (VSMCs). Thus, the ET_B receptor may participate in the differentiation of VSMCs.

Key Words: transactivation • EGF receptor • ERK1/2 • differentiation