Coinduction of Endothelial Nitric Oxide Synthase and Arginine Recycling Enzymes in Aorta of Diabetic Rats

Oyadomari, Seiichi; Gotoh, Tomomi; Aoyagi, Kazumasa; Araki, Eiichi; Shichiri, Motoaki; Mori, Masataka

doi:10.1006/niox.2001.0344

Cited by 57 publications

(47 citation statements)

References 37 publications

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“…Our study also demonstrates that diabetes can affect eNOS expression and activity in rat vSMC. As a matter of fact, we observed increased eNOS mRNA levels and increased total NOS activity in vSMC from DR. As far as increased eNOS expression is concerned, our data are consistent with those reported by several groups, showing increased eNOS protein content in the aortic wall of DR (Hink et al, 2001;Oyadomari et al, 2001). Regarding the observed increase in NOS activity, it is important to point out that the increased total NOS activity observed in vSMC from DR has to be attributed mainly, if not solely, to eNOS activity, since in cells from both diabetic and non-diabetic animals in the basal state we could not detect iNOS expression (data not shown).…”

Section: Discussionsupporting

confidence: 95%

“…Furthermore, although endothelial cells are by far the main site of vascular NO synthesis, vSMC do express NOSs and NO synthesis in vSMC might be important in vessel's function (Luoma et al, 1998;Papapetropoulos et al, 1999;Trovati et al, 1999). However, little is known about the expression of constitutive NOS in vSMC and its modulation in diabetes and/or in experimental conditions mimicking diabetes in vitro (Sugimoto et al, 1998;Hink et al, 2001;Oyadomari et al, 2001).…”

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confidence: 95%

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Phenotype modulation in cultures of vascular smooth muscle cells from diabetic rats: Association with increased nitric oxide synthase expression and superoxide anion generation

Pandolfi

Grilli

Cilli

et al. 2003

Journal Cellular Physiology

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Proliferative modification of vascular smooth muscle cell (vSMC) and impaired bioavailability of nitric oxide (NO) have both been proposed among the mechanisms linking diabetes and atherosclerosis. However, diabetes induced modifications in phenotype and nitric oxide synthase(s) (NOS) expression and activity in vSMC have not been fully characterized. In this study, cell morphology, proliferative response to serum, alpha-SMactin levels, eNOS expression and activity, cGMP intracellular content, and superoxide anion release were measured in cultures of vSMC obtained from aorta medial layer of ten diabetic (90% pancreatectomy, DR) and ten control (sham surgery, CR) rats. Vascular SMC from DR showed a less evident "hill and valley" culture morphology, increased growth response to serum, greater saturation density, and lower levels of alpha-SMactin. In the same cells, as compared to CR cells, eNOS mRNA levels and NOS activity were increased, while intracellular cGMP level was lower and superoxide anion production was significantly greater. These data indicate that chronic hyperglycemia might induce, in the vascular wall, an increased number of vSMC proliferative clones which persist in culture and are associated with increased eNOS expression and activity. However, upregulation of eNOS and increased NO synthesis occur in the presence of a marked concomitant increase of O(2-) production. Since NO bioavailability, as reflected by cGMP levels, was not increased in DR cells, it is tempting to hypothesize that the proliferative phenotype observed in DR cells is associated with a redox imbalance responsible quenching and/or trapping of NO, with the consequent loss of its biological activity.

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Section: Discussionsupporting

confidence: 95%

mentioning

confidence: 95%

Phenotype modulation in cultures of vascular smooth muscle cells from diabetic rats: Association with increased nitric oxide synthase expression and superoxide anion generation

Pandolfi

Grilli

Cilli

et al. 2003

Journal Cellular Physiology

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“…6). Published data on eNOS expression in diabetes are controversial [9, 32, 33], although most studies report no significant difference in eNOS mRNA between diabetic and non-diabetic vascular tissues. On the other hand, decreased NO availability in diabetes is attributed mainly to its interaction with reactive oxygen species [34, 35].…”

Section: Discussionmentioning

confidence: 99%

Augmented Contractile Response of Vascular Smooth Muscle in a Diabetic Mouse Model

Okon

Szado²,

Laher³

et al. 2003

J Vasc Res

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The vasomotor properties of isolated aortae and mesenteric arteries of insulin-resistant ob/ob and 57CBL/6J mice were compared in organ bath studies. Vessels from ob/ob mice were more sensitive to phenylephrine. Pretreatment with L-NAME caused similar leftward shifts of the phenylephrine concentration response curves in diabetic and non-diabetic vessels. The ob/ob aortae contracted in response to phenylephrine with roughly twice the force while they were not stiffer than control aortae. L-NAME caused a greater percentage increase in maximal force in the control than in the ob/ob tissue. Denudation potentiated force in the control aortae, but not in the ob/ob aortae. Endothelium-dependent relaxation in the ob/ob aortae and mesenteric arteries was impaired as manifested by a decreased sensitivity and maximal relaxation to acetylcholine, while the aortic basal eNOS mRNA levels did not differ between the two strains. In addition, ob/ob aortae were less sensitive to the nitric oxide donor sodium nitroprusside. Inhibition of endogenous prostaglandin synthesis with indomethacin (10 µM) partly normalized the contractile response of the ob/ob aortae and enhanced their endothelium-dependent relaxation. Neither blockade of endothelin-1 receptors (bosentan, 10 µM) nor PKC inhibition (calphostin, 1 µM) affected the contractile response to phenylephrine in the mouse aortae of either strain. In conclusion, vascular dysfunction in the aorta and mesenteric artery of ob/ob mice are due to increased smooth muscle contractility and impaired dilation but not to changes in elasticity of the vascular wall. Endothelium-produced prostaglandins contribute to the increased vasoconstriction.

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“…Although it has been demonstrated that diabetes is associated with endothelial dysfunction and it is known that endothelial-dependent vasodilation is significantly impaired in diabetic patients [102][103][104], whether and in which way elevated glucose levels might affect NO synthesis and bioavailability is still a matter of controversy [6,104,105]. The impaired endothelium-mediated vasodilation observed in diabetic patients might suggest a deficit in NO synthesis in these subjects.…”

Section: Regulation Of Vascular Nos Levels and Activity By Glucosementioning

confidence: 91%

Chronic hyperglicemia and nitric oxide bioavailability play a pivotal role in pro-atherogenic vascular modifications

Pandolfi

Filippis

2007

Genes Nutr

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Diabetes is associated with accelerated atherosclerosis and macrovascular complications are a major cause of morbidity and mortality in this disease. Although our understanding of vascular pathology has lately greatly improved, the mechanism(s) underlying enhanced atherosclerosis in diabetes remain unclear. Endothelial cell dysfunction is emerging as a key component in the pathophysiology of cardiovascular abnormalities associated with diabetes. Although it has been established that endothelium plays a critical role in overall homeostasis of the vessels, vascular smooth muscle cells (vSMC) in the arterial intima have a relevant part in the development of atherosclerosis in diabetes. However, high glucose induced alterations in vSMC behaviour are not fully characterized. Several studies have reported that impaired nitric oxide (NO) synthesis and/or actions are often present in diabetes and endothelial dysfunction. Furthermore, although endothelial cells are by far the main site of vascular NO synthesis, vSMC do express nitric oxyde synthases (NOSs) and NO synthesis in vSMC might be important in vessel's function. Although it is known that vSMC contribute to vascular pathology in diabetes by their change from a quiescent state to an activated proliferative and migratory phenotype (termed phenotypic modulation), whether this altered phenotypic modulation might also involve alterations in the nitrergic systems is still controversial. Our recent data indicate that, in vivo, chronic hyperglycemia might induce an increased number of vSMC proliferative clones which persist in culture and are associated with increased eNOS expression and activity. However, upregulation of eNOS and increased NO synthesis occur in the presence of a marked concomitant increase of O(2-) production. Since NO bioavailabilty might not be increased in high glucose stimulated vSMC, it is tempting to hypothesize that the proliferative phenotype observed in cells from diabetic rats is associated with a redox imbalance responsible quenching and/or trapping of NO, with the consequent loss of its biological activity. This might provide new insight on the mechanisms responsible for accelerated atherosclerosis in diabetes.

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Coinduction of Endothelial Nitric Oxide Synthase and Arginine Recycling Enzymes in Aorta of Diabetic Rats

Cited by 57 publications

References 37 publications

Phenotype modulation in cultures of vascular smooth muscle cells from diabetic rats: Association with increased nitric oxide synthase expression and superoxide anion generation

Phenotype modulation in cultures of vascular smooth muscle cells from diabetic rats: Association with increased nitric oxide synthase expression and superoxide anion generation

Augmented Contractile Response of Vascular Smooth Muscle in a Diabetic Mouse Model

Chronic hyperglicemia and nitric oxide bioavailability play a pivotal role in pro-atherogenic vascular modifications

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