Nitric oxide mediates tightening of the endothelial barrier by ascorbic acid

May, James M.; Qu, Zhi-chao

doi:10.1016/j.bbrc.2010.12.046

Cited by 29 publications

(23 citation statements)

References 31 publications

(34 reference statements)

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“…ASC is also important for maintaining the general function of the blood brain barrier (BBB) [75, 76]. Breakdown or disruptions of the BBB are found in normal aging [77] and AD [78, 79] and are associated with memory loss [80, 81].…”

Section: Discussionmentioning

confidence: 99%

Intravenous ascorbate improves spatial memory in middle-aged APP/PSEN1 and wild type mice

Kennard

Harrison

2014

Behavioural Brain Research

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The present study investigated the effects of a single intravenous (i.v.) dose of Vitamin C (ascorbate, ASC) on spatial memory in APP/PSEN1 mice, an Alzheimer's disease model. First, we confirmed the uptake time course in ASC-depleted gulo (−/−) mice, which cannot synthesize ASC. Differential tissue uptake was seen based on ASC transporter distribution. Liver (SVCT1 & SVCT2) ASC was elevated at 30, 60 and 120 min post-treatment (125 mg/kg, i.v.), whereas spleen (SVCT2) ASC increased at 60 and 120 min. There was no detectable change in cortical (SVCT2 at choroid plexus, and neurons) ASC within the 2-hour interval, although the cortex preferentially retained ASC. APP/PSEN1 and wild type (WT) mice at three ages (3, 9, or 20 months) were treated with ASC (125 mg/kg, i.v.) or saline 45 min before testing on the Modified Y-maze, a two-trial task of spatial memory. Memory declined with age and ASC treatment improved performance in 9 month-old APP/PSEN1 and WT mice. APP/PSEN1 mice displayed no behavioral impairment relative to WT controls. Although dopamine and metabolite DOPAC decreased in the nucleus accumbens with age, and improved spatial memory was correlated with increased dopamine in saline treated mice, acute ASC treatment did not alter monoamine levels in the nucleus accumbens. These data show that the Modified Y-maze is sensitive to age-related deficits, but not additional memory deficits due to amyloid pathology in APP/PSEN1 mice. They also suggest improvements in short-term spatial memory were not due to changes in the neuropathological features of AD or monoamine signaling.

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Section: Discussionmentioning

confidence: 99%

Intravenous ascorbate improves spatial memory in middle-aged APP/PSEN1 and wild type mice

Kennard

Harrison

2014

Behavioural Brain Research

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“…In this regard, we have shown that vitamin C, or ascorbic acid, prevents endothelial barrier leakage due to oxidized low density lipoprotein [14] and more recently due to thrombin [15]. Although ascorbate is considered an important cellular antioxidant, in both basal [16] and thrombin-activated cells [15], the vitamin enhanced the function of eNOS to generate nitric oxide (NO). It is known from a previous study that ascorbate promotes NO generation by recycling the crucial eNOS co-factor tetrahydrobiopterin [17].…”

Section: Introductionmentioning

confidence: 99%

Ascorbic acid prevents VEGF-induced increases in endothelial barrier permeability

et al. 2015

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Vascular endothelial growth factor (VEGF) increases endothelial barrier permeability, an effect that may contribute to macular edema in diabetic retinopathy. Since vitamin C, or ascorbic acid, can tighten the endothelial permeability barrier, we examined whether it could prevent the increase in permeability due to VEGF in human umbilical vein endothelial cells (HUVECs). As previously observed, VEGF increased HUVEC permeability to radiolabeled inulin within 60 min in a concentration-dependent manner. Loading the cells with increasing concentrations of ascorbate progressively prevented the leakage caused by 100 ng/ml VEGF, with a significant inhibition at 13 μM and complete inhibition at 50 μM. Loading cells with 100 μM ascorbate also decreased basal generation of reactive oxygen species and prevented the increase caused by both 100 ng/ml VEGF. VEGF treatment decreased intracellular ascorbate by 25%, thus linking ascorbate oxidation to its prevention of VEGF-induced barrier leakage. The latter was blocked by treating the cells with 60 μM L-NAME (but not D-NAME) as well as by 30 μM sepiapterin, a precursor of tetrahydrobiopterin that is required for proper function of endothelial nitric oxide synthase (eNOS). These findings suggest that VEGF-induced barrier leakage uncouples eNOS. Ascorbate inhibition of the VEGF effect could thus be due either to scavenging superoxide or to peroxynitrite generated by the uncoupled eNOS, or more likely to its ability to recycle tetrahydrobiopterin, thus avoiding enzyme uncoupling in the first place. Ascorbate prevention of VEGF-induced increases in endothelial permeability opens the possibility that its repletion could benefit diabetic macular edema.

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“…This effect occurs over 90 minutes and is not due to longer term increases in collagen matrix deposition [105], which had previously been observed for ascorbate in HUVECs [106]. The mechanism by which ascorbate decreases basal endothelial barrier permeability appears to require NO, since it was prevented by inhibition of either eNOS or downstream guanylate cyclase [107]. Increases in ascorbate to what are likely physiologic intracellular concentrations (1-2 mM) in HUVECs also prevented/reversed increases in endothelial barrier permeability caused by known oxidative stressors, including H 2 O 2 [108], oxidized low density lipoprotein [109], and intracellular ferric iron [110].…”

Section: Ascorbate Functions That May Decrease Pericyte Loss and Endomentioning

confidence: 90%

Ascorbic acid repletion: A possible therapy for diabetic macular edema?

May

2016

Free Radical Biology and Medicine

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Macular edema poses a significant risk for visual loss in persons with diabetic retinopathy. It occurs when plasma constituents and fluid leak out of damaged retinal microvasculature in the area of the macula, causing loss of central vision. Apoptotic loss of pericytes surrounding capillaries is perhaps the earliest feature of diabetic vascular damage in the macula, which is also associated with dysfunction of the endothelium and loss of the otherwise very tight endothelial permeability barrier. Increased oxidative stress is a key feature of damage to both cell types, mediated by excess superoxide from glucose-induced increases in mitochondrial metabolism, as well as by activation of the receptor for advanced glycation end products (RAGE). The latter in turn activates multiple pathways, some of which lead to increased oxidative stress, such as those involving NF-κB, NADPH oxidase, and endothelial nitric oxide synthase. Such cellular oxidative stress is associated with low cellular and plasma ascorbic acid levels in many subjects with diabetes in poor glycemic control. Whether repletion of low ascorbate in retinal endothelium and pericytes might help to prevent diabetic macular edema is unknown. However, cell culture studies show that the vitamin prevents high-glucose and RAGE-induced apoptosis in both cell types, that it preserves nitric oxide generated by endothelial cells, and that it tightens the leaky endothelial permeability barrier. Although these findings need to be confirmed in pre-clinical animal studies, it is worth considering clinical trials to determine whether adequate ascorbate repletion is possible and whether it might help to delay or even reverse early diabetic macular edema.

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Nitric oxide mediates tightening of the endothelial barrier by ascorbic acid

Cited by 29 publications

References 31 publications

Intravenous ascorbate improves spatial memory in middle-aged APP/PSEN1 and wild type mice

Intravenous ascorbate improves spatial memory in middle-aged APP/PSEN1 and wild type mice

Ascorbic acid prevents VEGF-induced increases in endothelial barrier permeability

Ascorbic acid repletion: A possible therapy for diabetic macular edema?

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