Intracellular mechanism of highd-glucose-induced modulation of vascular cell proliferation

Graier, Wolfgang F.; Grubenthal, Isabella; Dittrich, P.; Wascher, Thomas C.; Kostner, Gerhard M.

doi:10.1016/0014-2999(95)00534-x

Cited by 61 publications

(52 citation statements)

References 36 publications

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“…The increased replication rate of VSMC in high ambient glucose is consistent with the results of others [10,42]. In a study with hepatic stellate cells, malondialdehyde added to the substratum of the cells led to an increase in growth [43]; this provides evidence that products of free radical damage can stimulate cellular growth, at least when added exogenously.…”

Section: Discussionsupporting

confidence: 87%

“…Their growth and proliferation in the arterial intima is one key feature in the atherosclerotic lesion [9] and hyperproliferation has also been shown in VSMC cultured in high glucose concentrations [10]. There is evidence to suggest that reactive oxygen intermediates can act as stimulants of proliferation for VSMC [10,11], although there are a number of other recognised factors such as insulin [12], protein kinase C [13], and potent growth factors such as platelet-derived growth factor, fibroblast growth factor and heparin-binding epidermal growth factor-like growth factor [14]. The gene expression of the third potent growth factor can be increased by oxidative stress [14] and oxidant-mediated activation of protein kinase C has also been reported [15].…”

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confidence: 99%

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The effects of glucose-induced oxidative stress on growth and extracellular matrix gene expression of vascular smooth muscle cells

et al. 1998

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Diabetes mellitus is a major risk factor for atherosclerosis. In population based studies diabetes is associated with an increased incidence of coronary heart disease [1], cerebrovascular disease and peripheral vascular disease [2]. The high prevalence of macrovascular disease is partly explained by the increased frequency of conventional risk factors and partly by risk factors specific for diabetes including hyperglycaemia, hyperinsulinaemia and dyslipidaemia. The view that diabetic vasculopathy is, at least in part, related to excess free radicals is supported by evidence such as increased lipid peroxidation [3] and reduced antioxidant reserve in patients with diabetes [4] and from studies showing a direct cytotoxic effect of free Diabetologia (1998) Summary Vascular smooth muscle cell (VSMC) dysfunction plays a role in diabetic macrovasculopathy and this may include abnormalities in growth characteristics and the extracellular matrix. As the actual mechanisms by which glucose induces VSMC dysfunction remain unclear, the aim of this study was to assess the potential role of glucose-induced oxidative stress. Porcine aortic VSMCs were cultured for 10 days in either 5 mmol/l normal glucose or 25 mmol/l D-glucose (high glucose). There was evidence of oxidative stress as indicated by a 50 % increase in intracellular malondialdehyde (p < 0.05), increased mRNA expression of CuZn superoxide dismutase and Mn superoxide dismutase (by 51 % and 37 % respectively, p < 0.01) and a 50 % decrease in glutathione in 25 mmol/l D-glucose (p < 0.001). Growth was increased by 25.0 % (p < 0.01). mRNA expression of extracellular matrix proteins (collagens I, III, IV and fibronectin) was not altered by high glucose in these experimental conditions. Repletion of glutathione with N-acetyl L-cysteine (1 mmol/l) in VSMC grown in high glucose was associated with reduction in malondialdehyde and restored growth to that of normal glucose. The water soluble analogue of vitamin E, Trolox (200 mmol/l), reduced malondialdehyde concentrations, but had no effect on glutathione depletion or the increased growth rate seen with high glucose. The addition of buthionine sulphoximine (10 mmol/l) to VSMC cultured in normal glucose reduced glutathione, increased malondialdehyde and increased growth to a similar extent as that found in high glucose alone. These results suggest that thiol status, rather than lipid peroxides, is a key factor in modulating VSMC growth and that mRNA expression of extracellular matrix proteins is not increased in VSMC under conditions of glucose-induced oxidative stress. [Diabetologia (1998

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Section: Discussionsupporting

confidence: 87%

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confidence: 99%

The effects of glucose-induced oxidative stress on growth and extracellular matrix gene expression of vascular smooth muscle cells

et al. 1998

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“…It is clear that there is a dependence on cell type. For exam- ple, in one laboratory, differences were found between endothelial cells, the proliferation of which was inhibited by glucose, and smooth muscle cells, which responded to high glucose by increasing the proliferation rate (42). In another report, MCF7 human breast cells were sensitive to glucose, whereas MCF7 multidrug-resistant variant cells were not (34).…”

Section: Discussionmentioning

confidence: 99%

Glucose Effects on Skin Keratinocytes

et al. 2001

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Altered skin wound healing is a common cause of morbidity and mortality among diabetic patients. However, the molecular mechanisms whereby diabetes alters skin physiology have not been elucidated. In this study, we investigated the relative roles of hyperglycemia, insulin, and IGF-I, all of which are abnormal in diabetes, in primary murine skin keratinocytes. These cells proliferate and differentiate in vitro in a manner similar to skin in vivo. It was found that in the presence of high glucose (20 mmol/l), the glucose transport rate of primary proliferating or differentiating keratinocytes was downregulated, whereas at 2 mmol/l glucose, the transport rate was increased. These changes were associated with changes in the GLUT1 expression and with changes in the affinity constant (K m ) of the transport. Exposure to high glucose was associated with changes in cellular morphology, as well as with decreased proliferation and enhancement of Ca 2؉ -induced differentiation of keratinocytes. Furthermore, in the presence of high glucose, ligand-induced IGF-I receptor but not insulin receptor (IR) autophosphorylation was decreased. Consequently, in high glucose, the effects of IGF-I on glucose uptake and keratinocyte proliferation were inhibited. Interestingly, lack of IR expression in IR-null keratinocytes abolished insulin-induced glucose uptake and partially decreased insulin-and IGF-I-induced proliferation, demonstrating the direct involvement of the IR in these processes. Our results demonstrate that hyperglycemia and impaired insulin signaling might be directly involved in the development of chronic complications of diabetes by impairing glucose utilization of skin keratinocytes as well as skin proliferation and differentiation.

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“…Hyperglycaemia in vitro has similar anti-proliferative effects whether endothelial cells are obtained from microvessels or larger vessels [44,45]. Excessive glycation of extracellular matrix produced by human umbilical vein endothelial cells, cultured in high concentrations of glucose, might explain impaired adhesion of pericytes subsequently grown on matrices [46].…”

Section: Discussionmentioning

confidence: 99%

Enhanced fetoplacental angiogenesis in pre-gestational diabetes mellitus: the extra growth is exclusively longitudinal and not accompanied by microvascular remodelling

Mayhew

2002

Diabetologia

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Aims/hypothesis. Morphometric studies on pregnancies complicated by gestational diabetes mellitus have found no evidence of increased fetoplacental angiogenesis. Here, placentas from control subjects and patients with pre-gestational Type I (insulin-dependent) diabetes mellitus were used to test for differences in measures of angiogenesis and vascular remodelling. Methods. Term placentas were collected from non-diabetic subjects and well-controlled diabetic patients grouped according to duration and severity into White classes B, C, D and F/R. Tissues were obtained by uniform random sampling for position and orientation. Volumes, surface areas and lengths of peripheral villi and their capillaries were estimated stereologically. Comparisons were drawn by analysis of variance and used to interpret mechanisms of growth, villous capillarization and vessel remodelling. Results. Placentas associated with all classes of diabetes contained greater (19-45%) volumes of fetal capillaries attributable solely to increases in the combined length of capillaries (12-47%) and not to alteration of vessel cross-sectional area or perimeter. Longitudinal growth tended to increase capillarization (capillary:villus length ratios up to 19% larger) but changes were inconsistent between diabetic classes. There was no evidence of altered vascular remodelling (cross-sectional shape factors, perimeter 2 /area, were preserved). Conclusions/interpretations. In well-controlled pre-gestational diabetes, fetoplacental angiogenesis is enhanced and occurs exclusively by longitudinal growth. Differences may involve hypoxic or other metabolic effects on endothelial cells, perivascular cells and angiogenic factors. The findings differ from those previously reported in gestational diabetes. No differences were associated exclusively with the presence of diabetic complications.

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Intracellular mechanism of highd-glucose-induced modulation of vascular cell proliferation

Cited by 61 publications

References 36 publications

The effects of glucose-induced oxidative stress on growth and extracellular matrix gene expression of vascular smooth muscle cells

The effects of glucose-induced oxidative stress on growth and extracellular matrix gene expression of vascular smooth muscle cells

Glucose Effects on Skin Keratinocytes

Enhanced fetoplacental angiogenesis in pre-gestational diabetes mellitus: the extra growth is exclusively longitudinal and not accompanied by microvascular remodelling

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