Endothelial dysfunction in diabetes mellitus

Chakir, M; Plante, Gérard E.

doi:10.1016/s0952-3278(96)90080-0

Cited by 22 publications

(10 citation statements)

References 42 publications

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“…This hypoxia-induced state is believed to cause functional alterations in various cell types, including glial cells, endothelial cells, retinal pigment epithelial cells, vascular smooth muscle cells, fibroblasts, and inflammatory cells. However, the primary target of glucose-induced dysfunction is endothelial cells (Chakir and Plante, 1996;De Vriese et al, 2001;Hink et al, 2001;King et al, 1994) and they are therefore most susceptible to proliferating signals.…”

Section: Introductionmentioning

confidence: 99%

Growth Factors in Proliferative Diabetic Retinopathy

Khan

Chakrabarti

2003

Journal of Diabetes Research

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Many growth factors are implicated in the pathogenesis of proliferative diabetic retinopathy. Alteration of growth factors and their receptors in diabetes has been shown in both experimental and clinical studies. Sustained hyperglycemia resulting from long-standing diabetes leads to several biochemical abnormalities that consequently result in retinal hypoxia. Retinal oxygenation state regulates various growth factors that promote angiogenesis in order to meet the oxygen demands of the tissue. However, unregulated expression of these growth factors and induction of complex cascades leading to augmentation of other proangiogenic factors, which may not be regulated by tissue oxygenation, leads to uncontrolled retinal neovascularization and blindness in diabetic patients.

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Section: Introductionmentioning

confidence: 99%

Growth Factors in Proliferative Diabetic Retinopathy

Khan

Chakrabarti

2003

Journal of Diabetes Research

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“…The endothelium is an early target in diabetes, and dysfunction of vascular endothelial cells has a role in the diabetic vascular disease process (4). For example, the release of vasodilator and antiproliferative mediators such as nitric oxide and prostaglandin-I 2 is decreased, whereas production of endothelin-1 (ET-1) is increased (5).…”

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confidence: 99%

Type 2 Diabetes Causes Remodeling of Cerebrovasculature via Differential Regulation of Matrix Metalloproteinases and Collagen Synthesis

et al. 2005

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The risk of cerebrovascular disease is four-to sixfold higher in patients with diabetes. Vascular remodeling, characterized by extracellular matrix deposition and an increased media-to-lumen ratio, occurs in diabetes and contributes to the development of complications. However, diabetes-induced changes in the cerebrovascular structure remain unknown. Endothelin-1 (ET-1), a potent vasoconstrictor with profibrotic properties, is chronically elevated in diabetes. To determine diabetesmediated changes in the cerebrovasculature and the role of ET-1 in this process, type 2 diabetic GotoKakizaki (GK) rats were administered an ET A receptor antagonist for 4 weeks. Middle cerebral arteries were harvested and studies were performed to determine vascular structure. Tissue and plasma ET-1 levels were increased in GK rats compared with controls. Significant medial hypertrophy and collagen deposition resulted in an increased wall-to-lumen ratio in diabetic rats that was reduced by ET A receptor antagonism. Vascular matrix metalloproteinase (MMP)-2 activity was higher, but MMP-1 levels were significantly reduced in GK rats, and MMP levels were restored to control levels by ET A receptor antagonism. We conclude that ET-1 promotes cerebrovascular remodeling in type 2 diabetes through differential regulation of MMPs. Augmented cerebrovascular remodeling may contribute to an increased risk of stroke in diabetes, and ET A receptor antagonism may offer a novel therapeutic target. Diabetes 54:2638 -2644, 2005 T ype 2 diabetes, a disease that affects more than 17 million Americans, holds a two-to sixfold increased risk for cerebrovascular disease and stroke (1,2), and 70% of patients with a recent stroke have overt diabetes or pre-diabetes characterized by impaired fasting glucose or impaired glucose tolerance (3). However, the underlying basis of this predisposition remains unclear. Diabetic vascular complications are associated with remodeling of the vessel wall in the retinal, renal, and mesenteric circulations. However, diabetesinduced structural changes in the cerebral microvessels are unknown.The endothelium is an early target in diabetes, and dysfunction of vascular endothelial cells has a role in the diabetic vascular disease process (4). For example, the release of vasodilator and antiproliferative mediators such as nitric oxide and prostaglandin-I 2 is decreased, whereas production of endothelin-1 (ET-1) is increased (5). A significant correlation has been observed between plasma ET-1 levels and diabetes complications. In addition to being vasoconstrictive, ET-1 is also mitogenic. In streptozotocin-induced diabetes, nonselective ET receptor antagonism prevents extracellular matrix deposition in the retina as well as in the mesenteric arteries, providing evidence for a causal relationship (6,7). Nonselective blockade of ET receptors also prevents increased myogenic tone of cerebral vessels in diabetes (8), but the effect on vascular structure and the underlying mechanisms remain to be identified.The matrix metalloproteinases ...

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“…However, the focal point of research on diabetic nephropathy has been the glomerulus (15,38,39), and the prospect of significant injury to postglomerular capillaries has received less attention. Investigators have proposed that postglomerular microvessels are damaged in diabetic nephropathy (6), and some experimental support has been advanced (2,16), prompting the suggestion that damage to peritubular capillaries alters tubular function (16). However, peritubular vasculopathy has the potential of being far more detrimental, as compromised delivery of oxygen and nutrients is potentially lethal to renal tubules (11,19).…”

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confidence: 99%

Microcirculation: nexus of comorbidities in diabetes

Temm¹,

Dominguez²

2007

American Journal of Physiology-Renal Physiology

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Generalized capillary dysfunction is a morbid element in the metabolic syndrome, and it is likely involved in its complications. We tested the hypothesis that vast amounts of serum albumin previously observed in kidneys of rats with the metabolic syndrome were caused, in part, by leakage from renal peritubular capillaries. We report herein large scale leaks of plasma fluid in peritubular capillaries of rats with the metabolic syndrome. This finding was directly demonstrated in vivo, and the presence of leftover albumin residue confirmed the leak in postmortem kidney specimens. Moreover, renal interstitial fibrosis and tubular atrophy were found in a distribution similar to the leaked renal albumin in obese rats. We suggest that there is an important link between peritubular capillary damage and interstitial fibrosis, represented as tubulointerstitial disease in the metabolic syndrome. We propose that maintenance of the peritubular microcirculation may improve renal outcomes in diabetes and the metabolic syndrome. diabetic nephropathies; capillary permeability GENERALIZED CAPILLARY DYSFUNCTION is an important pathogenic mechanism of nephropathy and other complications of uncontrolled diabetes (6, 27). One logical inference from this notion is that glomerular and peritubular capillaries are similarly damaged in diabetic nephropathy. However, the focal point of research on diabetic nephropathy has been the glomerulus (15,38,39), and the prospect of significant injury to postglomerular capillaries has received less attention. Investigators have proposed that postglomerular microvessels are damaged in diabetic nephropathy (6), and some experimental support has been advanced (2, 16), prompting the suggestion that damage to peritubular capillaries alters tubular function (16). However, peritubular vasculopathy has the potential of being far more detrimental, as compromised delivery of oxygen and nutrients is potentially lethal to renal tubules (11,19). In fact, chronic peritubular capillary insufficiency might be a major contributor to tubular death and to interstitial fibrosis (1), both common features of progressive nephropathy in the metabolic syndrome (7,8).Capillary leaks of hearts, kidneys, and retinas have been described with various degrees of precision in diabetic rats (21,31,37), affirming the view that capillary damage is at least a component, if not an important source, of diabetes complications. We recently found large quantities of rat serum albumin in kidneys of male rats with nephropathy of the metabolic syndrome (7) and hypothesized a severe leakage of blood plasma into the renal interstitium, most likely from postglomerular capillaries. Hence, we searched for postglomerular capillary leakage of macromolecules in male rats with nephropathy of the metabolic syndrome. We studied F 1 generation hybrid male rats, the product of Zucker diabetic fatty (ZDF) and spontaneous hypertensive heart failure rats (ZS rats) which prominently depict all common features of the metabolic syndrome (7). We used two-photon ...

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Endothelial dysfunction in diabetes mellitus

Cited by 22 publications

References 42 publications

Growth Factors in Proliferative Diabetic Retinopathy

Growth Factors in Proliferative Diabetic Retinopathy

Type 2 Diabetes Causes Remodeling of Cerebrovasculature via Differential Regulation of Matrix Metalloproteinases and Collagen Synthesis

Microcirculation: nexus of comorbidities in diabetes

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