title: Vascular neuronal NO synthase is selectively upregulated by platelet-derived growth factor: involvement of the MEK/ERK pathway.
abstract: 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.
  
  
  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.
authors.affiliation: Second Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Sei
authors.initials: S
authors.lastname: Nakata
authors.forename: Masato
authors.initials: M
authors.lastname: Tsutsui
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
authors.forename: Masahito
authors.initials: M
authors.lastname: Tamura
authors.forename: Hiromi
authors.initials: H
authors.lastname: Tasaki
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Morishita
authors.forename: Osamu
authors.initials: O
authors.lastname: Suda
authors.forename: Susumu
authors.initials: S
authors.lastname: Ueno
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Toyohira
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Nakashima
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yanagihara
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology*; D009566:Nitrates / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D009573:Nitrites / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D007375:Interleukin-1; D009566:Nitrates; D009573:Nitrites; D010982:Platelet-Derived Growth Factor; D014662:Vasoconstrictor Agents; D013481:Superoxides; D000804:Angiotensin II; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496321:Nos1 protein, mouse; C496315:Nos3 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases