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(Circulation Research. 1999;85:565-574.)
© 1999 American Heart Association, Inc.

Molecular Medicine

Angiotensin II Stimulates Platelet-Derived Growth Factor-B Chain Expression in Newborn Rat Vascular Smooth Muscle Cells and Neointimal Cells Through Ras, Extracellular Signal–Regulated Protein Kinase, and c-Jun N-Terminal Protein Kinase Mechanisms

Jun-o Deguchi, Masatoshi Makuuchi, Takashi Nakaoka, Tucker Collins, Yoh Takuwa

From the Departments of Molecular and Cellular Physiology (J.D.), Surgery (J.D., M.M.), and Internal Medicine (T.N.), Graduate School of Medicine, University of Tokyo, Japan; Department of Physiology, Kanazawa University School of Medicine (Y.T.), Kanazawa, Japan; and Vascular Research Division, Department of Pathology, Brigham and Women's Hospital (T.C.), Boston, Mass.

Correspondence to Yoh Takuwa, MD, Department of Physiology, Kanazawa University School of Medicine, 13-1 Takara-machi, Kanazawa 920-8640, Japan. E-mail ytakuwa{at}med.kanazawa-u.ac.jp

Abstract—Platelet-derived growth factors (PDGFs) have been implicated in the pathogenesis of vascular proliferative disorders. Vascular smooth muscle cells (VSMCs) are one of the cell types that produce PDGF-B chain in proliferative lesions, although the mechanism of regulation of PDGF-B chain production in these cells is not well understood. In the present study, we demonstrate that angiotensin II (Ang II), which is also implicated in vascular stenosis after angioplasty and atherosclerosis, markedly stimulates PDGF-B chain mRNA expression in cultured newborn rat medial VSMCs and neointimal VSMCs via an AT₁, but not in adult rat VSMCs. In newborn rat VSMCs, Ang II activates extracellular signal–regulated protein kinase (ERK), c-Jun N-terminal protein kinase (JNK), and p38 mitogen–activated protein kinase. The mitogen-activated protein/ERK (MEK) inhibitor PD98059, but not the p38 inhibitor SB203580, abrogates Ang II–induced PDGF-B mRNA expression. Transient transfection analysis using a PDGF-B promoter-luciferase gene reporter construct reveals that Ang II induces transcriptional activation of PDGF-B chain gene, which is abolished by the expression of a dominant negative form of either ERK or JNK, but not of p38. The expression of a dominant negative form of Ras abolishes the stimulatory effects of Ang II on ERK activity and PDGF-B mRNA expression. In adult rat VSMCs, Ang II activates ERK and JNK, but weakly induces Egr-1, a transcription factor implicated in PDGF-B chain gene expression, compared with newborn VSMCs. These data indicate that Ang II activates PDGF-B chain gene expression in VSMCs through mechanisms involving Ras-ERK and JNK.

Key Words: angiotensin II • platelet-derived growth factor B chain • vascular smooth muscle • Ras • mitogen-activated protein kinase

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