VEGF increases BMEC monolayer permeability by affecting occludin expression and tight junction assembly

Wang, Wen; Dentler, William L.; Borchardt, Ronald T.

doi:10.1152/ajpheart.2001.280.1.h434

Cited by 248 publications

(162 citation statements)

References 22 publications

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“…This growth factor has been shown to alter the expression pattern of specific tight junction proteins in endothelial cells. 28,29 In addition, studies have demonstrated that increased vascular permeability in experimental diabetes is associated with reduced endothelial occludin content. 30 VEGF has been shown to cause rapid phosphorylation of occludin, which correlates with an increase in permeability between endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinases in early diabetic retinopathy and their role in alteration of the blood–retinal barrier

Giebel

Menicucci

McGuire

et al. 2005

Laboratory Investigation

282

232

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One of the early features of diabetic retinopathy is the alteration of the blood-retinal barrier (BRB), which may involve the breakdown of endothelial cell tight junctions. The aim of this study was to examine the expression of extracellular proteinases in an animal model of early diabetic retinopathy and to determine their role in the alteration of the BRB. Matrix metalloproteinase (MMP) expression was studied in the retinas of rats with 12 weeks of diabetes. The role of MMPs in regulating tight junction function was investigated in retinal endothelial and pigment epithelial cells by measuring transepithelial electrical resistance (TER). The retinas of diabetic animals demonstrated elevated levels of MMP-2, MMP-9 and MMP-14 messenger RNA. A significant increase in the production of MMP-9 was seen when cells were exposed to high glucose conditions. Both cell types treated with purified MMP-2 or MMP-9 were found to have alterations of tight junction function as shown by decreased TER. Western blot analysis of cell extracts treated with MMP-2 or MMP-9, revealed specific degradation of the tight junction protein, occludin. Results suggest that elevated expression of MMPs in the retina may facilitate an increase in vascular permeability by a mechanism involving proteolytic degradation of the tight junction protein occludin followed by disruption of the overall tight junction complex.

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Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinases in early diabetic retinopathy and their role in alteration of the blood–retinal barrier

Giebel

Menicucci

McGuire

et al. 2005

Laboratory Investigation

282

232

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“…However, it has been shown that neuroprotection and angiogenesis induced by VEGF monotherapy do not necessarily occur at the same dose of exogenous VEGF (Manoonkitiwongsa et al, 2004). Consequently, it would be necessarily, in the future, to investigate the role of endogenous VEGF and Ang-1 and to determine whether an optimal parenchymal concentration of both agents can safely stimulate both angiogenesis and neuroprotection in relation with an increase in functional outcome (Hori et al, 2004;Iizasa et al, 2002;Wang et al, 2001). However, Ang-1 might be also of interest for thrombolytic therapy for stroke.…”

Section: Discussionmentioning

confidence: 99%

VEGF-Induced BBB Permeability is Associated with an MMP-9 Activity Increase in Cerebral ischemia: Both Effects Decreased by ANG-1

Valable

Montaner

Bellail

et al. 2005

J Cereb Blood Flow Metab

177

125

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After cerebral ischemia, angiogenesis, by supplying for the deficient perfusion, may be a beneficial process for limiting neuronal death and promoting tissue repair. In this study, we showed that the combination of Ang-1 and vascular endothelial growth factor (VEGF) provides a more adapted therapeutic strategy than the use of VEGF alone. Indeed, we showed on a focal ischemia model that an early administration of VEGF exacerbates ischemic damage, because of its effects on bloodbrain barrier (BBB) permeability. In contrast, a coapplication of Ang-1 and VEGF leads to a significant reduction of the ischemic and edema volumes by 50% and 42%, respectively, in comparison with VEGF-treated mice. We proposed that Ang-1 blocks the BBB permeability effect of VEGF in association with a modulation of matrix metalloproteinase (MMP) activity. Indeed, we showed on both ischemic in vivo and BBB in vitro models that VEGF enhances BBB damage and MMP-9 activity and that Ang-1 counteracts both effects. However, we also showed a synergic angiogenic effect of Ang-1 and VEGF in the brain. Taken together, these results allow to propose that, in cerebral ischemia, the combination of Ang-1 and VEGF could be used early to promote the formation of mature neovessels without inducing side effects on BBB permeability.

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“…In vitro studies have shown VEGF-mediated reduction in expression of the tight junction proteins occludin and zona occludin-1 (28,29), which may be a primary reason for the increased permeability of the blood-brain barrier when VEGF expression is increased. However, other contributory factors could include increased expression of the aquaporin 4 water channel in astrocytes (30), and downregulation of angiopoietin-1, an important accessory protein for neovascularization and producing stable blood vessel structure, which is also correlated with increased blood-brain barrier leakage (31).…”

Section: Microvasculature and Fetal Hypoxiamentioning

confidence: 99%

VEGF expression and microvascular responses to severe transient hypoxia in the fetal sheep brain

2012

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Background: Fetal hypoxia contributes significantly to the pathogenesis of permanent perinatal brain injury. We hypothesized that hypoxia-induced cerebral angiogenesis and microvascular changes would occur in fetal sheep subjected to a severe hypoxic insult produced by umbilical cord occlusion (UcO) for 10 min. Methods: at 124-126 d of gestation, singleton fetal sheep underwent surgery for implantation of catheters and placement of an inflatable cuff around the umbilical cord. a 10-min UcO or sham UcO (n = 5) was induced at 130 d gestation. The fetal brain was collected at 24 h (n = 5) or 48 h (n = 4) after UcO for immunohistochemical analysis of vascular endothelial growth factor (VeGF), Ki67, and serum albumin. results: By 48 h after UcO, the percentage of blood vessels expressing VeGF had increased in the subventricular zone, periventricular and subcortical white matter, corpus callosum, and cortex. alterations in vascular permeability (albumin extravasation) were observed only in the periventricular and subcortical white matter and the subventricular zone following UcO. conclusion: The upregulation of VeGF expression and increased leakage of plasma protein in the fetal sheep brain show that the microvasculature in white matter is sensitive to hypoxia in the near-term brain.

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VEGF increases BMEC monolayer permeability by affecting occludin expression and tight junction assembly

Cited by 248 publications

References 22 publications

Matrix metalloproteinases in early diabetic retinopathy and their role in alteration of the blood–retinal barrier

Matrix metalloproteinases in early diabetic retinopathy and their role in alteration of the blood–retinal barrier

VEGF-Induced BBB Permeability is Associated with an MMP-9 Activity Increase in Cerebral ischemia: Both Effects Decreased by ANG-1

VEGF expression and microvascular responses to severe transient hypoxia in the fetal sheep brain

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