Ascorbic acid prevents VEGF-induced increases in endothelial barrier permeability
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 perm...
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description | 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 the 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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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 the 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.</description><identifier>ISSN: 0300-8177</identifier><identifier>EISSN: 1573-4919</identifier><identifier>DOI: 10.1007/s11010-015-2609-6</identifier><identifier>PMID: 26590088</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Antioxidants - pharmacology ; Ascorbic Acid - pharmacology ; Biochemistry ; Biomedical and Life Sciences ; Cardiology ; Cellular biology ; Diabetic retinopathy ; Edema ; Endothelium ; Endothelium, Vascular - physiology ; Enzymes ; Human Umbilical Vein Endothelial Cells ; Humans ; Life Sciences ; Medical Biochemistry ; Nitric oxide ; Nitric Oxide - physiology ; Oncology ; Oxidative stress ; Permeability ; Prevention ; Protein expression ; Superoxides ; Vascular endothelial growth factor ; Vascular Endothelial Growth Factor A - physiology ; Vitamin C</subject><ispartof>Molecular and cellular biochemistry, 2016-01, Vol.412 (1-2), p.73-79</ispartof><rights>Springer Science+Business Media New York 2015</rights><rights>COPYRIGHT 2016 Springer</rights><rights>Springer Science+Business Media New York 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c673t-a9f40b094caffba92424ba0481c84cff8da259ea29724d2b426c6b9dd663c9e63</citedby><cites>FETCH-LOGICAL-c673t-a9f40b094caffba92424ba0481c84cff8da259ea29724d2b426c6b9dd663c9e63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s11010-015-2609-6$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s11010-015-2609-6$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,780,784,885,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26590088$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ulker, Esad</creatorcontrib><creatorcontrib>Parker, William H.</creatorcontrib><creatorcontrib>Raj, Amita</creatorcontrib><creatorcontrib>Qu, Zhi-chao</creatorcontrib><creatorcontrib>May, James M.</creatorcontrib><title>Ascorbic acid prevents VEGF-induced increases in endothelial barrier permeability</title><title>Molecular and cellular biochemistry</title><addtitle>Mol Cell Biochem</addtitle><addtitle>Mol Cell Biochem</addtitle><description>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 the 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.</description><subject>Antioxidants - pharmacology</subject><subject>Ascorbic Acid - pharmacology</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Cardiology</subject><subject>Cellular biology</subject><subject>Diabetic retinopathy</subject><subject>Edema</subject><subject>Endothelium</subject><subject>Endothelium, Vascular - physiology</subject><subject>Enzymes</subject><subject>Human Umbilical Vein Endothelial Cells</subject><subject>Humans</subject><subject>Life Sciences</subject><subject>Medical Biochemistry</subject><subject>Nitric oxide</subject><subject>Nitric Oxide - physiology</subject><subject>Oncology</subject><subject>Oxidative stress</subject><subject>Permeability</subject><subject>Prevention</subject><subject>Protein expression</subject><subject>Superoxides</subject><subject>Vascular endothelial growth factor</subject><subject>Vascular Endothelial Growth Factor A - 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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 the 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.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>26590088</pmid><doi>10.1007/s11010-015-2609-6</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Antioxidants - pharmacology Ascorbic Acid - pharmacology Biochemistry Biomedical and Life Sciences Cardiology Cellular biology Diabetic retinopathy Edema Endothelium Endothelium, Vascular - physiology Enzymes Human Umbilical Vein Endothelial Cells Humans Life Sciences Medical Biochemistry Nitric oxide Nitric Oxide - physiology Oncology Oxidative stress Permeability Prevention Protein expression Superoxides Vascular endothelial growth factor Vascular Endothelial Growth Factor A - physiology Vitamin C |
title | Ascorbic acid prevents VEGF-induced increases in endothelial barrier permeability |
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