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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2502.)
© 2005 American Heart Association, Inc.

Vascular Biology

Vascular Neuronal NO Synthase Is Selectively Upregulated by Platelet-Derived Growth Factor

Involvement of the MEK/ERK Pathway

Sei Nakata; Masato Tsutsui; Hiroaki Shimokawa; Masahito Tamura; Hiromi Tasaki; Tsuyoshi Morishita; Osamu Suda; Susumu Ueno; Yumiko Toyohira; Yasuhide Nakashima; Nobuyuki Yanagihara

From the Second Department of Internal Medicine (S.N., M.T., H.T., T.M., O.S., Y.N.) and the Department of Pharmacology (M.T., S.U., Y.T., N.Y.), School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan; and the Department of Cardiovascular Medicine (H.S.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.

Correspondence to Masato Tsutsui, MD, PhD, Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan. E-mail mt2498{at}med.uoeh-u.ac.jp

Objective— We demonstrated recently that neuronal NO synthase (NOS) is expressed in arteriosclerotic lesions and exerts important vasculoprotective effects in vivo. In this study, we examined the molecular mechanism(s) for vascular neuronal NOS (nNOS) expression.

Methods and Results— In cultured rat aortic smooth muscle cells, treatment with platelet-derived growth factor (PDGF) selectively upregulated nNOS expression but not inducible NOS (iNOS) or endothelial NOS (eNOS) expression. Treatment with PDGF also significantly caused activation of mitogen-activated protein kinase (MAPK) family, including extracellular signal-regulated kinase (ERK), p38MAPK, and c-Jun N-terminal kinase (JNK). ERK kinase (MAPK kinase [MEK]) inhibitors inhibited PDGF-induced nNOS expression, whereas a p38MAPK inhibitor or JNK inhibitor was without effects. Importantly, gene transfer of MEK per se elicited nNOS induction, and gene transfer of dominant-negative MEK abolished PDGF-induced nNOS expression. In isolated aortas of wild-type, eNOS^–/–, and iNOS^–/– mice, but not in those of nNOS^–/– mice, treatment with PDGF significantly enhanced nNOS expression and nitrite plus nitrate production, both of which were again attenuated by a MEK inhibitor.

Conclusions— These results provide the first evidence that vascular nNOS expression is upregulated selectively in response to PDGF through the MEK/ERK pathway. Upregulated nNOS may play an important compensatory role under arteriosclerotic/inflammatory conditions associated with eNOS dysfunction to maintain vascular homeostasis.

This study demonstrates that vascular neuronal NO synthase (nNOS) expression is selectively upregulated in response to platelet-derived growth factor via activation of the ERK cascade. Upregulated nNOS may play an important compensatory role in the presence of reduced endothelial NOS activity (eg, arteriosclerosis) to maintain vascular homeostasis.

Key Words: ERK • mitogen-activated protein kinase • neuronal nitric oxide synthase • nitric oxide • platelet-derived growth factor

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