Role of Vitamin C in the Function of the Vascular Endothelium
Publication: Antioxidants & Redox Signaling
Volume 19, Issue Number 17
Abstract
Significance: Vitamin C, or ascorbic acid, has long been known to participate in several important functions in the vascular bed in support of endothelial cells. These functions include increasing the synthesis and deposition of type IV collagen in the basement membrane, stimulating endothelial proliferation, inhibiting apoptosis, scavenging radical species, and sparing endothelial cell-derived nitric oxide to help modulate blood flow. Although ascorbate may not be able to reverse inflammatory vascular diseases such as atherosclerosis, it may well play a role in preventing the endothelial dysfunction that is the earliest sign of many such diseases. Recent Advances: Beyond simply preventing scurvy, evidence is mounting that ascorbate is required for optimal function of many dioxygenase enzymes in addition to those involved in collagen synthesis. Several of these enzymes regulate the transcription of proteins involved in endothelial function, proliferation, and survival, including hypoxia-inducible factor-1α and histone and DNA demethylases. More recently, ascorbate has been found to acutely tighten the endothelial permeability barrier and, thus, may modulate access of ascorbate and other molecules into tissues and organs. Critical Issues: The issue of the optimal cellular content of ascorbate remains unresolved, but it appears that low millimolar ascorbate concentrations are normal in most animal tissues, in human leukocytes, and probably in the endothelium. Although there may be little benefit of increasing near maximal cellular ascorbate concentrations in normal people, many diseases and conditions have either systemic or localized cellular ascorbate deficiency as a cause for endothelial dysfunction, including early atherosclerosis, sepsis, smoking, and diabetes. Future Directions: A key focus for future studies of ascorbate and the vascular endothelium will likely be to determine the mechanisms and clinical relevance of ascorbate effects on endothelial function, permeability, and survival in diseases that cause endothelial dysfunction. Antioxid. Redox Signal. 19, 2068–2083.
Get full access to this article
View all available purchase options and get full access to this article.
References
1.
Aguirre R and May JM. Inflammation in the vascular bed: importance of vitamin C. Pharmacol Ther 119: 96–103, 2008.
2.
Agus DB, Gambhir SS, Pardridge WM, Speilholz C, Baselga J, and Vera JC. Vitamin C crosses the blood-brain barrier in the oxidized form through the glucose transporters. J Clin Invest 100: 2842–2848, 1997.
3.
Albelda SM, Sampson PM, Haselton FR, McNiff JM, Mueller SN, Williams SK, Fishman AP, and Levine EM. Permeability characteristics of cultured endothelial cell monolayers. J Appl Physiol 64: 308–322, 1988.
4.
Antonov AS, Lukashev ME, Romanov YA, Tkachuk VA, Repin VS, and Smirnov VN. Morphological alterations in endothelial cells from human aorta and umbilical vein induced by forskolin and phorbol 12-myristate 13-acetate: a synergistic action of adenylate cyclase and protein kinase C activators. Proc Natl Acad Sci U S A 83: 9704–9708, 1986.
5.
Arrigoni O and De Tullio MC. Ascorbic acid: much more than just an antioxidant. Biochim Biophys Acta Gen Subj 1569: 1–9, 2002.
6.
Ashino H, Shimamura M, Nakajima H, Dombou M, Kawanaka S, Oikawa T, Iwaguchi T, and Kawashima S. Novel function of ascorbic acid as an angiostatic factor. Angiogenesis 6: 259–269, 2003.
7.
Assefa F, Jabarkhil MZ, Salama P, and Spiegel P. Malnutrition and mortality in Kohistan District, Afghanistan, April 2001. JAMA 286: 2723–2728, 2001.
8.
Babaev VR, Whitesell RR, Li L, Linton MF, Fazio S, and May JM. Selective macrophage ascorbate deficiency suppresses early atherosclerosis. Free Radic Biol Med 50: 27–36, 2011.
9.
Barnes MJ, Constable BJ, and Kodicek E. Excretion of hydroxyproline and other amino acids in scorbutic guinea-pigs. Biochim Biophys Acta 184: 358–365, 1969.
10.
Barnes MJ, Constable BJ, and Kodicek E. Studies in vivo on the biosynthesis of collagen and elastin in ascorbic acid-deficient guinea pigs. Biochem J 113: 387–397, 1969.
11.
Bazzoni G. Endothelial tight junctions: permeable barriers of the vessel wall. Thromb Haemost 95: 36–42, 2006.
12.
Becker BF, Reinholz N, Ozcelik T, Leipert B, and Gerlach E. Uric acid as radical scavenger and antioxidant in the heart. Pflugers Arch 415: 127–135, 1989.
13.
Beckman JS and Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and the ugly. Am J Physiol Cell Physiol 271: C1424–C1437, 1996.
14.
Bergsten P, Amitai G, Kehrl J, Dhariwal KR, Klein HG, and Levine M. Millimolar concentrations of ascorbic acid in purified human mononuclear leukocytes. Depletion and reaccumulation. J Biol Chem 265: 2584–2587, 1990.
15.
Best KA, Holmes ME, Samson SE, Mwanjewe J, Wilson JX, Dixon SJ, and Grover AK. Ascorbate uptake in pig coronary artery endothelial cells. Mol Cell Biochem 271: 43–49, 2005.
16.
Bianchi J, Wilson FA, and Rose RC. Dehydroascorbic acid and ascorbic acid transport systems in the quinea pig ileum. Am J Physiol 250: G461–G468, 1986.
17.
Bielski BH, Richter HW, and Chan PC. Some properties of the ascorbate free radical. Ann N Y Acad Sci 258: 231–237, 1975.
18.
Bisby RH and Parker AW. Reaction of ascorbate with the α-tocopheroxyl radical in micellar and bilayer membrane systems. Arch Biochem Biophys 317: 170–178, 1995.
19.
Bode AM, Cunningham L, and Rose RC. Spontaneous decay of oxidized ascorbic acid (dehydro-L-ascorbic acid) evaluated by high-pressure liquid chromatography. Clin Chem 36: 1807–1809, 1990.
20.
Boyer JC, Campbell CE, Sigurdson WJ, and Kuo SM. Polarized localization of vitamin C transporters, SVCT1 and SVCT2, in epithelial cells. Biochem Biophys Res Commun 334: 150–156, 2005.
21.
Bruick RK and McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294: 1337–1340, 2001.
22.
Bruick RK and McKnight SL. Transcription. Oxygen sensing gets a second wind. Science 295: 807–808, 2002.
23.
Bruno RS, Leonard SW, Atkinson J, Montine TJ, Ramakrishnan R, Bray TM, and Traber MG. Faster plasma vitamin E disappearance in smokers is normalized by vitamin C supplementation. Free Radic Biol Med 40: 689–697, 2006.
24.
Buettner GR. The pecking order of free radicals and antioxidants: lipid peroxidation, alpha-tocopherol, and ascorbate. Arch Biochem Biophys 300: 535–543, 1993.
25.
Buettner GR and Jurkiewicz BA. Catalytic metals, ascorbate and free radicals: Combinations to avoid. Radiat Res 145: 532–541, 1996.
26.
Burstyn JN, Yu AE, Dierks EA, Hawkins BK, and Dawson JH. Studies of the heme coordination and ligand binding properties of soluble guanylyl cyclase (sGC): characterization of Fe(II)sGC and Fe(II)sGC(CO) by electronic absorption and magnetic circular dichroism spectroscopies and failure of CO to activate the enzyme. Biochemistry 34: 5896–5903, 1995.
27.
Cahill L, Corey PN, and El Sohemy A. Vitamin C deficiency in a population of young Canadian adults. Am J Epidemiol 170: 464–471, 2009.
28.
Carr A and Frei B. Does vitamin C act as a pro-oxidant under physiological conditions? FASEB J 13: 1007–1024, 1999.
29.
Cash TP, Pan Y, and Simon MC. Reactive oxygen species and cellular oxygen sensing. Free Radic Biol Med 43: 1219–1225, 2007.
30.
Chatterjee IB. Biosynthesis of L-ascorbate in animals. Methods Enzymol 18: 28–34, 1970.
31.
Cherian S, Jameson S, Rajarajeswari C, Helena V, Latha L, Anu Rekha MR, Nagamma T, Subba R V, Kini PG, and Rao A. Oxidative stress in sepsis in children. Indian J Med Res 125: 143–148, 2007.
32.
Chung TL, Brena RM, Kolle G, Grimmond SM, Berman BP, Laird PW, Pera MF, and Wolvetang EJ. Vitamin C Promotes Widespread Yet Specific DNA Demethylation of the Epigenome in Human Embryonic Stem Cells. Stem Cells 28: 1848–1855, 2010.
33.
Chung TL, Turner JP, Thaker NY, Kolle G, Cooper-White JJ, Grimmond SM, Pera MF, and Wolvetang EJ. Ascorbate promotes epigenetic activation of CD30 in human embryonic stem cells. Stem Cells 28: 1782–1793, 2010.
34.
Constantinescu A, Han D, and Packer L. Vitamin E recycling in human erythrocyte membranes. J Biol Chem 268: 10906–10913, 1993.
35.
Cook NR, Albert CM, Gaziano JM, Zaharris E, MacFadyen J, Danielson E, Buring JE, and Manson JE. A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: results from the Women's Antioxidant Cardiovascular Study. Arch Intern Med 167: 1610–1618, 2007.
36.
Crabtree MJ, Smith CL, Lam G, Goligorsky MS, and Gross SS. Ratio of 5,6,7,8-tetrahydrobiopterin to 7,8-dihydrobiopterin in endothelial cells determines glucose-elicited changes in NO vs. superoxide production by eNOS. Am J Physiol Heart Circ Physiol 294: H1530–H1540, 2008.
37.
Davis KA, Samson SE, Best K, Mallhi KK, Szewczyk M, Wilson JX, Kwan CY, and Grover AK. Ca(2+)-mediated ascorbate release from coronary artery endothelial cells. Br J Pharmacol 147: 131–139, 2006.
38.
De Caterina R, Libby P, Peng HB, Thannickal VJ, Rajavashisth TB, Gimbrone MA Jr., Shin WS, and Liao JK. Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest 96: 60–68, 1995.
39.
de Jong L, Albracht SP, and Kemp A. Prolyl 4-hydroxylase activity in relation to the oxidation state of enzyme-bound iron. The role of ascorbate in peptidyl proline hydroxylation. Biochim Biophys Acta 704: 326–332, 1982.
40.
Dejana E, Corada M, and Lampugnani MG. Endothelial cell-to-cell junctions. FASEB J 9: 910–918, 1995.
41.
Del Bello B, Maellaro E, Sugherini L, Santucci A, Comporti M, and Casini AF. Purification of NADPH-dependent dehydroascorbate reductase from rat liver and its identification with 3α-hydroxysteroid dehydrogenase. Biochem J 304: 385–390, 1994.
42.
Dhariwal KR, Hartzell WO, and Levine M. Ascorbic acid and dehydroascorbic acid measurements in human plasma and serum. Am J Clin Nutr 54: 712–716, 1991.
43.
DiLabio GA and Wright JS. Hemiketal formation of dehydroascorbic acid drives ascorbyl radical anion disproportionation. Free Radic Biol Med 29: 480–485, 2000.
44.
Doise JM, Aho LS, Quenot JP, Guilland JC, Zeller M, Vergely C, Aube H, Blettery B, and Rochette L. Plasma antioxidant status in septic critically ill patients: a decrease over time. Fundam Clin Pharmacol 22: 203–209, 2008.
45.
Domazou AS, Koppenol WH, and Gebicki JM. Efficient repair of protein radicals by ascorbate. Free Radic Biol Med 46: 1049–1057, 2009.
46.
Draijer R, Atsma DE, van der LA, and van Hinsbergh VW. cGMP and nitric oxide modulate thrombin-induced endothelial permeability. Regulation via different pathways in human aortic and umbilical vein endothelial cells. Circ Res 76: 199–208, 1995.
47.
Drake BB, Smythe CV, and King CG. Complexes of dehydroascorbic acid with three sulfhydryl compounds. J Biol Chem 143: 89–98, 1942.
48.
Duffy SJ, Gokce N, Holbrook M, Huang A, Frei B, Keaney JF Jr., and Vita JA. Treatment of hypertension with ascorbic acid. Lancet 354: 2048–2049, 1999.
49.
Duffy SJ, Gokce N, Holbrook M, Hunter LM, Biegelsen ES, Huang AO, Keaney JF Jr., and Vita JA. Effect of ascorbic acid treatment on conduit vessel endothelial dysfunction in patients with hypertension. Am J Physiol Heart Circ Physiol 280: H528–H534, 2001.
50.
Eipper BA and Mains RE. The role of ascorbate in the biosynthesis of neuroendocrine peptides. Am J Clin Nutr 54: 1153S–1156S, 1991.
51.
Englard S and Seifter S. The biochemical functions of ascorbic acid. Annu Rev Nutr 6: 365–406, 1986.
52.
Esteban MA, Wang T, Qin B, Yang J, Qin D, Cai J, Li W, Weng Z, Chen J, Ni S, et al. Vitamin C enhances the generation of mouse and human induced pluripotent stem cells. Cell Stem Cell 6: 71–79, 2010.
53.
Evans RM, Currie L, and Campbell A. The distribution of ascorbic acid between various cellular components of blood, in normal individuals, and its relation to the plasma concentration. Br J Nutr 47: 473–482, 1982.
54.
Ford ES, Mokdad AH, Giles WH, and Brown DW. The metabolic syndrome and antioxidant concentrations: findings from the Third National Health and Nutrition Examination Survey. Diabetes 52: 2346–2352, 2003.
55.
Frei B. Molecular and biological mechanisms of antioxidant action. FASEB J 13: 963–964, 1999.
56.
Fridovich I. Superoxide radical: an endogenous toxicant. Annu Rev Pharmacol Toxicol 23: 239–257, 1983.
57.
García ML, Salazar K, Millán C, Rodríguez F, Montecinos H, Caprile T, Silva C, Cortes C, Reinicke K, Vera JC, et al. Sodium vitamin C cotransporter SVCT2 is expressed in hypothalamic glial cells. Glia 50: 32–47, 2005.
58.
Geesin JC, Darr D, Kaufman R, Murad S, and Pinnell SR. Ascorbic acid specifically increases type I and type III procollagen messenger RNA levels in human skin fibroblast. J Invest Dermatol 90: 420–424, 1988.
59.
Gerken T, Girard CA, Tung YC, Webby CJ, Saudek V, Hewitson KS, Yeo GS, McDonough MA, Cunliffe S, McNeill LA, et al. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science 318: 1469–1472, 2007.
60.
Gokce N, Keaney JF Jr., Frei B, Holbrook M, Olesiak M, Zachariah BJ, Leeuwenburgh C, Heinecke JW, and Vita JA. Long-term ascorbic acid administration reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation 99: 3234–3240, 1999.
61.
Goss SPA, Hogg N, and Kalyanaraman B. The effect of α-tocopherol on the nitration of gamma-tocopherol by peroxynitrite. Arch Biochem Biophys 363: 333–340, 1999.
62.
Gotoh N and Niki E. Rates of interactions of superoxide with vitamin E, vitamin C and related compounds as measured by chemiluminescence. Biochim Biophys Acta 1115: 201–207, 1992.
63.
Grano A and De Tullio MC. Ascorbic acid as a sensor of oxidative stress and a regulator of gene expression: The Yin and Yang of vitamin C. Med Hypotheses 69: 953–954, 2007.
64.
Haendeler J, Zeiher AM, and Dimmeler S. Vitamin C and E prevent lipopolysaccharide-induced apoptosis in human endothelial cells by modulation of Bcl-2 and Bax. Eur J Pharmacol 317: 407–411, 1996.
65.
Halliwell B. Vitamin C: poison, prophylactic or panacea? Trends Biochem Sci 24: 255–259, 1999.
66.
Han M, Pendem S, Teh SL, Sukumaran DK, Wu F, and Wilson JX. Ascorbate protects endothelial barrier function during septic insult: Role of protein phosphatase type 2A. Free Radic Biol Med 48: 128–135, 2010.
67.
Hara T and Minakami S. On functional role of cytochrome b5. II. NADH-linked ascorbate radical reductase activity in microsomes. J Biochem (Tokyo) 69: 325–330, 1971.
68.
Harris AL. Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer 2: 38–47, 2002.
69.
Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360: 23–33, 2002.
70.
Heitzer T, Just H, and Münzel T. Antioxidant vitamin C improves endothelial dysfunction in chronic smokers. Circulation 94: 6–9, 1996.
71.
Heitzer T, Schlinzig T, Krohn K, Meinertz T, and Münzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 104: 2673–2678, 2001.
72.
Heller R, Unbehaun A, Schellenberg B, Mayer B, Werner-Felmayer G, and Werner ER. L-ascorbic acid potentiates endothelial nitric oxide synthesis via a chemical stabilization of tetrahydrobiopterin. J Biol Chem 276: 40–47, 2001.
73.
Ho FM, Liu SH, Lin WW, and Liau CS. Opposite effects of high glucose on MMP-2 and TIMP-2 in human endothelial cells. J Cell Biochem 101: 442–450, 2007.
74.
Horton JR, Upadhyay AK, Qi HH, Zhang X, Shi Y, and Cheng X. Enzymatic and structural insights for substrate specificity of a family of jumonji histone lysine demethylases. Nat Struct Mol Biol 17: 38–43, 2010.
75.
Hudson BG, Reeders ST, and Tryggvason K. Type IV collagen: structure, gene organization, and role in human diseases. Molecular basis of Goodpasture and Alport syndromes and diffuse leiomyomatosis. J Biol Chem 268: 26033–26036, 1993.
76.
Huie RE and Padmaja S. The reaction of no with superoxide. Free Radic Res Commun 18: 195–199, 1993.
77.
Iyanagi T and Yamazaki I. One-electron-transfer reactions in biochemical systems. 3. One- electron reduction of quinones by microsomal flavin enzymes. Biochim Biophys Acta 172: 370–381, 1969.
78.
Jackson TS, Xu AM, Vita JA, and Keaney JF, Jr. Ascorbate prevents the interaction of superoxide and nitric oxide only at very high physiological concentrations. Circ Res 83: 916–922, 1998.
79.
Kagan VE, Serbinova EA, Forte T, Scita G, and Packer L. Recycling of vitamin E in human low density lipoproteins. J Lipid Res 33: 385–397, 1992.
80.
Kaufmann PA, Gnecchi-Ruscone T, Di Terlizzi M, Schäfers KP, Lüscher TF, and Camici PG. Coronary heart disease in smokers—Vitamin C restores coronary microcirculatory function. Circulation 102: 1233–1238, 2000.
81.
Khan BV, Harrison DG, Olbrych MT, Alexander RW, and Medford RM. Nitric oxide regulates vascular cell adhesion molecule 1 gene expression and redox-sensitive transcriptional events in human vascular endothelial cells. Proc Natl Acad Sci U S A 93: 9114–9119, 1996.
82.
Kubes P, Suzuki M, and Granger DN. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A 88: 4651–4655, 1991.
83.
Kuzkaya N, Weissmann N, Harrison DG, and Dikalov S. Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols—Implications for uncoupling endothelial nitric-oxide synthase. J Biol Chem 278: 22546–22554, 2003.
84.
Kuzkaya N, Weissmann N, Harrison DG, and Dikalov S. Interactions of peroxynitrite with uric acid in the presence of ascorbate and thiols: implications for uncoupling endothelial nitric oxide synthase. Biochem Pharmacol 70: 343–354, 2005.
85.
Ladurner A, Schmitt CA, Schachner D, Atanasov AG, Werner ER, Dirsch VM, and Heiss EH. Ascorbate stimulates endothelial nitric oxide synthase enzyme activity by rapid modulation of its phosphorylation status. Free Radic Biol Med 52: 2082–2090, 2012.
86.
Langlois M, Duprez D, Delanghe J, De Buyzere M, and Clement DL. Serum vitamin C concentration is low in peripheral arterial disease and is associated with inflammation and severity of atherosclerosis. Circulation 103: 1863–1868, 2001.
87.
Leveque N, Robin S, Muret P, Mac-Mary S, Makki S, and Humbert P. High iron and low ascorbic acid concentrations in the dermis of atopic dermatitis patients. Dermatology 207: 261–264 2003.
88.
Levine SZ, Marples E, and Gordon HH. A defect in the metabolism of aromatic amino acids in premature infants: The role of vitamin C. Science 90: 620–621, 1939.
89.
Li L, Chen W, Rezvan A, Jo H, and Harrison DG. Tetrahydrobiopterin deficiency and nitric oxide synthase uncoupling contribute to atherosclerosis induced by disturbed flow. Arterioscler Thromb Vasc Biol 31: 1547–1554, 2011.
90.
Long CL, Maull KI, Krishnan RS, Laws HL, Geiger JW, Borghesi L, Franks W, Lawson TC, and Sauberlich HE. Ascorbic acid dynamics in the seriously ill and injured. J Surg Res 109: 144–148, 2003.
91.
Lumper L, Schneider W, and Staudinger H. Untersuchungen zur Kinetik der mikrosomalen NADH:Semidehydroascorbat-Oxydoreduktase. Hoppe Seylers Z Physiol Chem 348: 323–328, 1967.
92.
Lykkesfeldt J, Christen S, Wallock LM, Chang HH, Jacob RA, and Ames BN. Ascorbate is depleted by smoking and repleted by moderate supplementation: a study in male smokers and nonsmokers with matched dietary antioxidant intakes. Am J Clin Nutr 71: 530–536, 2000.
93.
Madruga d.O., Rondo PH, and Barros SB. Concentrations of ascorbic acid in the plasma of pregnant smokers and nonsmokers and their newborns. Int J Vitam Nutr Res 74: 193–198, 2004.
94.
Mahmoodian F and Peterkofsky B. Vitamin C deficiency in guinea pigs differentially affects the expression of type IV collagen, laminin, and elastin in blood vessels. J Nutr 129: 83–91, 1999.
95.
Martin A and Frei B. Both intracellular and extracellular vitamin C inhibit atherogenic modification of LDL by human vascular endothelial cells. Arterioscler Thromb Vasc Biol 17: 1583–1590, 1997.
96.
Maulen NP, Henriquez EA, Kempe S, Carcamo JG, Smid-Kotsas A, Bachem M, Grunen A, Bustamante ME, Nualart F, and Vera JC. Upregulation and polarized expression of the sodium-ascorbic acid transporter SVCT1 in post-confluent differentiated CaCo-2 cells. J Biol Chem 278: 9035–9041, 2003.
97.
May JM. How does ascorbic acid prevent endothelial dysfunction? Free Radic Biol Med 28: 1421–1429, 2000.
98.
May JM, Cobb CE, Mendiratta S, Hill KE, and Burk RF. Reduction of the ascorbyl free radical to ascorbate by thioredoxin reductase. J Biol Chem 273: 23039–23045, 1998.
99.
May JM, Li L, and Qu ZC. Oxidized LDL up-regulates the ascorbic acid transporter SVCT2 in endothelial cells. Mol Cell Biochem 343: 217–222, 2010.
100.
May JM, Mendiratta S, Hill KE, and Burk RF. Reduction of dehydroascorbate to ascorbate by the selenoenzyme thioredoxin reductase. J Biol Chem 272: 22607–22610, 1997.
101.
May JM, Qu Z, and Morrow JD. Mechanisms of ascorbic acid recycling in human erythrocytes. Biochim Biophys Acta 1528: 159–166, 2001.
102.
May JM and Qu ZC. Redox regulation of ascorbic acid transport: Role of transporter and intracellular sulfhydryls. Biofactors 20: 199–211, 2004.
103.
May JM and Qu ZC. Transport and intracellular accumulation of vitamin C in endothelial cells: relevance to collagen synthesis. Arch Biochem Biophys 434: 178–186, 2005.
104.
May JM and Qu ZC. Ascorbic acid efflux and re-uptake in endothelial cells: maintenance of intracellular ascorbate. Mol Cell Biochem 325: 79–88, 2009.
105.
May JM and Qu ZC. Ascorbic acid prevents increased endothelial permeability caused by oxidized low density lipoprotein. Free Radic Res 44: 1359–1368, 2010.
106.
May JM and Qu ZC. Nitric oxide mediates tightening of the endothelial barrier by ascorbic acid. Biochem Biophys Res Commun 404: 701–705, 2011.
107.
May JM, Qu ZC, and Li X. Requirement for GSH in recycling of ascorbic acid in endothelial cells. Biochem Pharmacol 62: 873–881, 2001.
108.
May JM, Qu ZC, and Qiao H. Transfer of ascorbic acid across the vascular endothelium: mechanism and self-regulation. Am J Physiol Cell Physiol 297: C169–C178, 2009.
109.
May JM, Qu ZC, Qiao H, and Koury MJ. Maturational loss of the vitamin C transporter in erythrocytes. Biochem Biophys Res Commun 360: 295–298, 2007.
110.
May JM, Qu Z-C, and Li X. Ascorbic acid blunts oxidant stress due to menadione in endothelial cells. Arch Biochem Biophys 411: 136–144, 2003.
111.
May JM, Qu Z-C, and Mendiratta S. Protection and recycling of α-tocopherol in human erythrocytes by intracellular ascorbic acid. Arch Biochem Biophys 349: 281–289, 1998.
112.
McNeish AJ, Wilson WS, and Martin W. Ascorbate blocks endothelium-derived hyperpolarizing factor (EDHF)-mediated vasodilatation in the bovine ciliary vascular bed and rat mesentery. Br J Pharmacol 135: 1801–1809, 2002.
113.
Menniti FS, Knoth J, and Diliberto EJ Jr. Role of ascorbic acid in dopamine beta-hydroxylation. The endogenous enzyme cofactor and putative electron donor for cofactor regeneration. J Biol Chem 261: 16901–16908, 1986.
114.
Mercier P and Ekindjian OG. Collagen type IV: major component of basement membranes. Current knowledge. Ann Biol Clin (Paris) 48: 695–711, 1990.
115.
Mikirova NA, Casciari JJ, and Riordan NH. Ascorbate inhibition of angiogenesis in aortic rings ex vivo and subcutaneous Matrigel plugs in vivo. J Angiogenes Res 2: 2, 2010.
116.
Millward TA, Zolnierowicz S, and Hemmings BA. Regulation of protein kinase cascades by protein phosphatase 2A. Trends Biochem Sci 24: 186–191, 1999.
117.
Mount PF, Kemp BE, and Power DA. Regulation of endothelial and myocardial NO synthesis by multi-site eNOS phosphorylation. J Mol Cell Cardiol 42: 271–279, 2007.
118.
Murad S, Grove D, Lindberg KA, Reynolds G, Sivarajah A, and Pinnell SR. Regulation of collagen synthesis by ascorbic acid. Proc Natl Acad Sci U S A 78: 2879–2882, 1981.
119.
Myllylä R, Kuutti-Savolainen ER, and Kivirikko KI. The role of ascorbate in the prolyl hydroxylase reaction. Biochem Biophys Res Commun 83: 441–448, 1978.
120.
Myllylä R, Tuderman L, and Kivirikko KI. Mechanism of the prolyl hydroxylase reaction. 2. Kinetic analysis of the reaction sequence. Eur J Biochem 80: 349–357, 1977.
121.
Nelson PJ, Pruitt RE, Henderson LL, Jenness R, and Henderson LM. Effect of ascorbic acid deficiency on the in vivo synthesis of carnitine. Biochim Biophys Acta 672: 123–127, 1981.
122.
Niki E, Noguchi N, Tsuchihashi H, and Gotoh N. Interaction among vitamin C, vitamin E, and β-carotene. Am J Clin Nutr 62 Suppl: 1322S–1326S, 1995.
123.
Nishikimi M. Oxidation of ascorbic acid with superoxide anion generated by the xanthine-xanthine oxidase system. Biochem Biophys Res Commun 63: 463–468, 1975.
124.
Nualart FJ, Rivas CI, Montecinos VP, Godoy AS, Guaiquil VH, Golde DW, and Vera JC. Recycling of vitamin C by a bystander effect. J Biol Chem 278: 10128–10133, 2003.
125.
Padayatty SJ and Levine M. Antioxidant supplements and cardiovascular disease in men. JAMA 301: 1336–1337, 2009.
126.
Pastore P, Rizzetto T, Curcuruto O, Cin MD, Zaramella A, and Marton D. Characterization of dehydroascorbic acid solutions by liquid chromatography/mass spectrometry. Rapid Commun Mass Spectrom 15: 2051–2057, 2001.
127.
Patel KB, Stratford MRL, Wardman P, and Everett SA. Oxidation of tetrahydrobiopterin by biological radicals and scavenging of the trihydrobiopterin radical by ascorbate. Free Radic Biol Med 32: 203–211, 2002.
128.
Predescu D, Predescu S, Shimizu J, Miyawaki-Shimizu K, and Malik AB. Constitutive eNOS-derived nitric oxide is a determinant of endothelial junctional integrity. Am J Physiol Lung Cell Mol Physiol 289: L371–L381, 2005.
129.
Price KD, Price CS, and Reynolds RD. Hyperglycemia-induced ascorbic acid deficiency promotes endothelial dysfunction and the development of atherosclerosis. Atherosclerosis 158: 1–12, 2001.
130.
Qiao H, Li L, Qu ZC, and May JM. Cobalt-induced oxidant stress in cultured endothelial cells: Prevention by ascorbate in relation to HIF-1alpha. Biofactors 35: 306–313, 2009.
131.
Qiao H and May JM. Development of ascorbate transport in brain capillary endothelial cells in culture. Brain Res 1208: 79–86, 2008.
132.
Rebouche CJ. Ascorbic acid and carnitine biosynthesis. Am J Clin Nutr 54: 1147S–1152S, 1991.
133.
Rixen H, Kirkpatrick CJ, Schmitz U, Ruchatz D, and Mittermayer C. Interaction between endothelial cells and basement membrane components. In vitro studies on endothelial cell adhesion to collagen types I, III, IV and high molecular weight fragments of IV. Exp Cell Biol 57: 315–323, 1989.
134.
Rössig L, Hoffmann J, Hugel B, Mallat Z, Haase A, Freyssinet JM, Tedgui A, Aicher A, Zeiher AM, and Dimmeler S. Vitamin C inhibits endothelial cell apoptosis in congestive heart failure. Circulation 104: 2182–2187, 2001.
135.
Sabharwal AK and May JM. alpha-Lipoic acid and ascorbate prevent LDL oxidation and oxidant stress in endothelial cells. Mol Cell Biochem 309: 125–132, 2008.
136.
Saeed RW, Peng T, and Metz CN. Ascorbic acid blocks the growth inhibitory effect of tumor necrosis factor-alpha on endothelial cells. Exp Biol Med (Maywood) 228: 855–865, 2003.
137.
Santus R, Patterson LK, Filipe P, Morliere P, Hug GL, Fernandes A, and Maziere JC. Redox reactions of the urate radical/urate couple with the superoxide radical anion, the tryptophan neutral radical and selected flavonoids in neutral aqueous solutions. Free Radic Res 35: 129–136, 2001.
138.
Schectman G, Byrd JC, and Gruchow HW. The influence of smoking on vitamin C status in adults. Am J Public Health 79: 158–162, 1989.
139.
Schor AM, Schor SL, and Allen TD. Effects of culture conditions on the proliferation, morphology and migration of bovine aortic endothelial cells. J Cell Sci 62: 267–285, 1983.
140.
Sen CK and Packer L. Antioxidant and redox regulation of gene transcription. FASEB J 10: 709–720, 1996.
141.
Seno T, Inoue N, Matsui K, Ejiri J, Hirata K, Kawashima S, and Yokoyama M. Functional expression of sodium-dependent vitamin C transporter 2 in human endothelial cells. J Vasc Res 41: 345–351, 2004.
142.
Sesso HD, Buring JE, Christen WG, Kurth T, Belanger C, MacFadyen J, Bubes V, Manson JE, Glynn RJ, and Gaziano JM. Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial. JAMA 300: 2123–2133, 2008.
143.
Shekhonin BV, Domogatsky SP, Idelson GL, Koteliansky VE, and Rukosuev VS. Relative distribution of fibronectin and type I, III, IV, V collagens in normal and atherosclerotic intima of human arteries. Atherosclerosis 67: 9–16, 1987.
144.
Sies H and Arteel GE. Interaction of peroxynitrite with selenoproteins and glutathione peroxidase mimics. Free Radic Biol Med 28: 1451–1455, 2000.
145.
Solzbach U, Hornig B, Jeserich M, and Just H. Vitamin C improves endothelial dysfunction of epicardial coronary arteries in hypertensive patients. Circulation 96: 1513–1519, 1997.
146.
Sotiriou S, Gispert S, Cheng J, Wang YH, Chen A, Hoogstraten-Miller S, Miller GF, Kwon O, Levine M, Guttentag SH, et al. Ascorbic-acid transporter Slc23a1 is essential for vitamin C transport into the brain and for perinatal survival. Nat Med 8: 514–517, 2002.
147.
Squadrito GL, Cueto R, Splenser AE, Valavanidis A, Zhang H, Uppu RM, and Pryor WA. Reaction of uric acid with peroxynitrite and implications for the mechanism of neuroprotection by uric acid. Arch Biochem Biophys 376: 333–337, 2000.
148.
Squadrito GL, Jin X, and Pryor WA. Stopped-flow kinetic study of the reaction of ascorbic acid with peroxynitrite. Arch Biochem Biophys 322: 53–59, 1995.
149.
Stewart LC and Klinman JP. Cooperativity in the dopamine beta-monooxygenase reaction. Evidence for ascorbate regulation of enzyme activity. J Biol Chem 266: 11537–11543, 1991.
150.
Stirrat A, Nelli S, Dowell FJ, and Martin W. Flow-induced enhancement of vasoconstriction and blockade of endothelium-derived hyperpolarizing factor (EDHF) by ascorbate in the rat mesentery. Br J Pharmacol 153: 1162–1168, 2008.
151.
Stoner L, Erickson ML, Young JM, Fryer S, Sabatier MJ, Faulkner J, Lambrick DM, and McCully KK. There's more to flow-mediated dilation than nitric oxide. J Atheroscler Thromb 19: 589–600, 2012.
152.
Sugiyama T, Levy BD, and Michel T. Tetrahydrobiopterin recycling, a key determinant of endothelial nitric-oxide synthase-dependent signaling pathways in cultured vascular endothelial cells. J Biol Chem 284: 12691–12700, 2009.
153.
Taddei S, Virdis A, Ghiadoni L, Magagna A, and Salvetti A. Vitamin C improves endothelium-dependent vasodilation by restoring nitric oxide activity in essential hypertension. Circulation 97: 2222–2229, 1998.
154.
Tamareille S, Mignen O, Capiod T, Rucker-Martin C, and Feuvray D. High glucose-induced apoptosis through store-operated calcium entry and calcineurin in human umbilical vein endothelial cells. Cell Calcium 39: 47–55, 2006.
155.
Tang VW and Goodenough DA. Paracellular ion channel at the tight junction. Biophys J 84: 1660–1673, 2003.
156.
Telang S, Clem AL, Eaton JW, and Chesney J. Depletion of ascorbic acid restricts angiogenesis and retards tumor growth in a mouse model. Neoplasia 9: 47–56, 2007.
157.
Thiele J, Rompcik V, Wagner S, and Fischer R. Vascular architecture and collagen type IV in primary myelofibrosis and polycythaemia vera: an immunomorphometric study on trephine biopsies of the bone marrow. Br J Haematol 80: 227–234, 1992.
158.
Tousoulis D, Antoniades C, Vasiliadou C, Kourtellaris P, Koniari K, Marinou K, Charakida M, Ntarladimas I, Siasos G, and Stefanadis C. Effects of atorvastatin and vitamin C on forearm hyperaemic blood flow, asymmentrical dimethylarginine levels and the inflammatory process in patients with type 2 diabetes mellitus. Heart 93: 244–246, 2007.
159.
Tousoulis D, Xenakis C, Tentolouris C, Davies G, Antoniades C, Crake T, and Stefanadis C. Effects of vitamin C on intracoronary L-arginine dependent coronary vasodilatation in patients with stable angina. Heart 91: 1319–1323, 2005.
160.
Tsukada Y, Fang J, Erdjument-Bromage H, Warren ME, Borchers CH, Tempst P, and Zhang Y. Histone demethylation by a family of JmjC domain-containing proteins. Nature 439: 811–816, 2006.
161.
Tsukaguchi H, Tokui T, Mackenzie B, Berger UV, Chen X.-Z., Wang YX, Brubaker RF, and Hediger MA. A family of mammalian Na+-dependent L-ascorbic acid transporters. Nature 399: 70–75, 1999.
162.
Upston JM, Karjalainen A, Bygrave FL, and Stocker R. Efflux of hepatic ascorbate: a potential contributor to the maintenance of plasma vitamin C. Biochem J 342: 49–56, 1999.
163.
Utoguchi N, Ikeda K, Saeki K, Oka N, Mizuguchi H, Kubo K, Nakagawa S, and Mayumi T. Ascorbic acid stimulates barrier function of cultured endothelial cell monolayer. J Cell Physiol 163: 393–399, 1995.
164.
Vasquez-Vivar J, Whitsett J, Martasek P, Hogg N, and Kalyanaraman B. Reaction of tetrahydrobiopterin with superoxide: EPR-kinetic analysis and characterization of the pteridine radical. Free Radic Biol Med 31: 975–985, 2001.
165.
Vera JC, Rivas CI, Fischbarg J, and Golde DW. Mammalian facilitative hexose transporters mediate the transport of dehydroascorbic acid. Nature 364: 79–82, 1993.
166.
Violi F and Cangemi R. Antioxidant supplements and cardiovascular disease in men. JAMA 301: 1335–1337, 2009.
167.
Vissers MC, Gunningham SP, Morrison MJ, Dachs GU, and Currie MJ. Modulation of hypoxia-inducible factor-1 alpha in cultured primary cells by intracellular ascorbate. Free Radic Biol Med 42: 765–772, 2007.
168.
Vissers MC and Wilkie RP. Ascorbate deficiency results in impaired neutrophil apoptosis and clearance and is associated with up-regulation of hypoxia-inducible factor 1{alpha}. J Leukoc Biol 81: 1236–1244, 2007.
169.
Voigt K, Kontush A, Stuerenburg HJ, Muench-Harrach D, Hansen HC, and Kunze K. Decreased plasma and cerebrospinal fluid ascorbate levels in patients with septic encephalopathy. Free Radic Res 36: 735–739, 2002.
170.
Wang S, Eide TC, Sogn EM, Berg KJ, and Sund RB. Plasma ascorbic acid in patients undergoing chronic haemodialysis. Eur J Clin Pharmacol 55: 527–532, 1999.
171.
Wang T, Chen K, Zeng X, Yang J, Wu Y, Shi X, Qin B, Zeng L, Esteban MA, Pan G, et al. The histone demethylases Jhdm1a/1b enhance somatic cell reprogramming in a vitamin-C-dependent manner. Cell Stem Cell 9: 575–587, 2011.
172.
Washko P and Levine M. Inhibition of ascorbic acid transport in human neutrophils by glucose. J Biol Chem 267: 23568–23574, 1992.
173.
Washko PW, Wang Y, and Levine M. Ascorbic acid recycling in human neutrophils. J Biol Chem 268: 15531–15535, 1993.
174.
Wells WW, Xu DP, Yang YF, and Rocque PA. Mammalian thioltransferase (glutaredoxin) and protein disulfide isomerase have dehydroascorbate reductase activity. J Biol Chem 265: 15361–15364, 1990.
175.
Westendorp RG, Draijer R, Meinders AE, and van Hinsbergh VW. Cyclic-GMP-mediated decrease in permeability of human umbilical and pulmonary artery endothelial cell monolayers. J Vasc Res 31: 42–51, 1994.
176.
Willis GC. An experimental study of the intimal ground substance in atherosclerosis. Can Med Assoc J 69: 17–22, 1953.
177.
Willis GC. The reversibility of atherosclerosis. Can Med Assoc J 77: 106–108, 1957.
178.
Winkler BS. In vitro oxidation of ascorbic acid and its prevention by GSH. Biochim Biophys Acta 925: 258–264, 1987.
179.
Winkler BS, Orselli SM, and Rex TS. The redox couple between glutathione and ascorbic acid: A chemical and physiological perspective. Free Radic Biol Med 17: 333–349, 1994.
180.
Winterbourn CC and Metodiewa D. The reaction of superoxide with reduced glutathione. Arch Biochem Biophys 314: 284–290, 1994.
181.
Witczak CA, Sharoff CG, and Goodyear LJ. AMP-activated protein kinase in skeletal muscle: from structure and localization to its role as a master regulator of cellular metabolism. Cell Mol Life Sci 65: 3737–3755, 2008.
182.
Wu F, Schuster DP, Tyml K, and Wilson JX. Ascorbate inhibits NADPH oxidase subunit p47phox expression in microvascular endothelial cells. Free Radic Biol Med 42: 124–131, 2007.
183.
Wu F and Wilson JX. Peroxynitrite-dependent activation of protein phosphatase type 2A mediates microvascular endothelial barrier dysfunction. Cardiovasc Res 81: 38–45, 2009.
184.
Yoshikawa K, Takahashi S, Imamura Y, Sado Y, and Hayashi T. Secretion of non-helical collagenous polypeptides of alpha1(IV) and alpha2(IV) chains upon depletion of ascorbate by cultured human cells. J Biochem (Tokyo) 129: 929–936, 2001.
185.
Zhang K, Dong J, Cheng X, Bai W, Guo W, Wu L, and Zuo L. Association between Vitamin C deficiency and dialysis modalities. Nephrology (Carlton) 17: 452–457, 2012.
Information & Authors
Information
Published In
Antioxidants & Redox Signaling
Volume 19 • Issue Number 17 • December 10, 2013
Pages: 2068 - 2083
PubMed: 23581713
Copyright
Copyright 2013, Mary Ann Liebert, Inc.
History
Published online: 16 December 2013
Published in print: December 10, 2013
Published ahead of print: 29 May 2013
Published ahead of production: 15 April 2013
Accepted: 14 April 2013
Revision received: 26 March 2013
Received: 22 January 2013
Topics
Authors
Metrics & Citations
Metrics
Citations
Export Citation
Export citation
Select the format you want to export the citations of this publication.
View Options
Get Access
Access content
To read the fulltext, please use one of the options below to sign in or purchase access.⚠ Society Access
If you are a member of a society that has access to this content please log in via your society website and then return to this publication.