Vasculoprotective roles of neuronal nitric oxide synthase.
Nitric oxide (NO) has multiple important actions that contribute to the maintenance of vascular homeostasis. NO is synthesized by three different isoforms of NO synthase (NOS), all of which have been reported to be expressed in human atherosclerotic vascular lesions. Although the regulatory roles of endothelial NOS (eNOS) and inducible NOS (iNOS) on the development of atherosclerosis have been described, little is known about the role of neuronal NOS (nNOS). Here, we show that nNOS also exerts important vasculoprotective effects in vivo. In a carotid artery ligation model, nNOS gene-deficient (nNOS-KO) mice exhibited accelerated neointimal formation and constrictive vascular remodeling caused by blood flow disruption. In a rat balloon injury model, the selective inhibition of nNOS activity potently enhanced vasoconstrictor responses to a variety of calcium-mobilizing stimuli, suppressed tissue cGMP concentrations, a marker of vascular NO production, and exacerbated neointimal formation. In both models, nNOS was absent before injury and was up-regulated only after the injury, and was predominantly expressed in the neointima and medial smooth muscle cells. These results provide the first direct evidence that nNOS plays important roles in suppressing arteriosclerotic vascular lesion formation in vivo.
Morishita
Tsuyoshi
T
Second Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan.
Tsutsui
Masato
M
Shimokawa
Hiroaki
H
Horiuchi
Masataka
M
Tanimoto
Akihide
A
Suda
Osamu
O
Tasaki
Hiromi
H
Huang
Paul L
PL
Sasaguri
Yasuyuki
Y
Yanagihara
Nobuyuki
N
Nakashima
Yasuhide
Y
D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D002339:Carotid Arteries / Q000201:enzymology / Q000473:pathology / Q000601:surgery; D006152:Cyclic GMP / Q000032:analysis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008026:Ligation; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I; D051381:Rats; D015854:Up-Regulation; D014661:Vasoconstriction
D004791:Enzyme Inhibitors; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; C496322:Nos1 protein, rat; D006152:Cyclic GMP; D002118:Calcium