title: Crucial vasculoprotective role of the whole nitric oxide synthase system in vascular lesion formation in mice: Involvement of bone marrow-derived cells.
abstract: Although all three nitric oxide (NO) synthases (nNOS, iNOS, and eNOS) are expressed in injured arteries, it remains to be elucidated the role of the NOSs in their entirety in the vascular lesion formation. We addressed this issue in mice deficient in all NOS genes. Vascular injury was induced by permanent ligation of a unilateral carotid artery in wild-type (WT), singly, and triply NOS(-/-) mice. Two weeks after the procedure, constrictive vascular remodeling and neointimal formation were recognized in the ligated arteries. While constrictive remodeling was noted in the nNOS(-/-) and iNOS(-/-) genotypes, it was most accelerated in the n/i/eNOS(-/-) genotype. While neointimal formation was evident in the eNOS(-/-) and nNOS(-/-) genotypes, it was also most aggravated in the n/i/eNOS(-/-) genotype. Those lesions were reversed by long-term treatment with isosorbide dinitrate, a NO donor. Finally, we examined the involvement of bone marrow-derived cells in the vascular lesion formation. Bone marrow from the WT, singly, or triply NOS(-/-) mice was transplanted into the WT mice, and then the carotid ligation was performed. Intriguingly, constrictive remodeling and neointimal formation were both similarly most exacerbated in the case of the n/i/eNOS(-/-) bone marrow transplantation. These results indicate that the complete disruption of all the NOS genes causes markedly accelerated vascular lesion formation caused by blood flow disruption in mice in vivo, demonstrating the crucial vasculoprotective role of the whole endogenous NOS system. Our findings also suggest that the NOS system in bone marrow-derived cells may be involved in this vasculoprotective mechanism.
authors.affiliation: Second Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Furuno
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Morishita
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Toyohira
authors.forename: Sohsuke
authors.initials: S
authors.lastname: Yamada
authors.forename: Susumu
authors.initials: S
authors.lastname: Ueno
authors.forename: Naoya
authors.initials: N
authors.lastname: Morisada
authors.forename: Kazunari
authors.initials: K
authors.lastname: Sugita
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Noguchi
authors.forename: Mayuko
authors.initials: M
authors.lastname: Sakanashi
authors.forename: Hironori
authors.initials: H
authors.lastname: Miyata
authors.forename: Akihide
authors.initials: A
authors.lastname: Tanimoto
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Sasaguri
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Otsuji
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yanagihara
authors.forename: Masahito
authors.initials: M
authors.lastname: Tamura
authors.forename: Masato
authors.initials: M
authors.lastname: Tsutsui
mesh_terms: D000818:Animals; D001794:Blood Pressure; D001854:Bone Marrow Cells / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D002339:Carotid Arteries / Q000601:surgery; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D008026:Ligation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009566:Nitrates / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism
chemical_list: D009566:Nitrates; D009573:Nitrites; D019001:Nitric Oxide Synthase