Browse > Article

Effects of Nitric Oxide Donor Supplementation on Copper Deficient Embryos and Nitric Oxide-Mediated Downstream Signaling  

Yang, Soo-Jin (Department of Nutrition, University of California at Davis)
Publication Information
Journal of Nutrition and Health / v.41, no.8, 2008 , pp. 691-700 More about this Journal
Abstract
One suggested mechanism underlying copper (Cu) deficiency teratogenicity is a low availability of nitric oxide (NO), signaling molecule which is essential in developmental processes. Increased superoxide anions secondary to decreased activities of Cu-zinc superoxide dismutase (Cu-Zn SOD) in Cu deficiency can interact with NO to form peroxynitrite, which can nitrate proteins at tyrosine residues. In addition, peroxynitrite formation can limit NO bioavailability. We previously reported low NO availability and increased protein nitration in Cu deficient (Cu-) embryos. In the current study, we tested whether Cu deficiency alters downstream signaling of NO by assessing cyclic GMP (cGMP) and phosphorylated vasodilator-stimulating phosphoprotein (VASP) levels, and whether NO supplementation can affect these targets as well as protein nitration. Gestation day 8.5 embryos from Cu adequate (Cu+) or Cu- dams were collected and cultured in either Cu+ or Cu- media for 48 hr. A subset of embryos was cultured in Cu- media supplemented with a NO donor (DETA/NONOate; 20 ${\mu}M$) and/or Cu-Zn SOD. Cu-/Cu- embryos showed a higher incidence of embryonic and yolk sac abnormalities, low NO availability, blunted dose-response in NO concentrations to increasing doses of acetylcholine, low mRNA expression of endothelial nitric oxide synthase (eNOS), increased levels of 3-nitrotyrosine (3-NT) compared to Cu+/Cu+ controls. cGMP concentrations tended to be low in Cu-/Cu- embryos, and they were significantly lower in Cu-/Cu- yolk sacs than in controls. Levels of phosphorylated VASP at serine 239 (P-VASP) were similar in all groups. NO donor supplementation to the Cu- media ameliorated embryonic and yolk sac abnormalities, and resulted in increased levels of cGMP without altering levels of P-VASP and 3-NT. Taken together, these data support the concept that Cu deficiency limits NO availability and alters NO/cGMP-dependent signaling in Cu- embryos and yolk sacs, which contributes to Cu deficiency-induced abnormal development.
Keywords
copper deficiency; nitric oxide; oxidative stress; cyclic GMP; phosphorylated vasodilator-stimulating phosphoprotein;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Hanafy KA, Krumenacker JS, Murad F. NO, nitrotyrosine, and cyclic GMP in signal transduction. Med Sci Monit 2001; 7(4):801-819
2 Nath AK, Enciso J, Kuniyasu M, Hao XY, Madri JA, Pinter E. Nitric oxide modulates murine yolk sac vasculogenesis and rescues glucose induced vasculopathy. Development 2004; 131(10): 2485-2496   DOI   ScienceOn
3 Fantel AG, Nekahi N, Shepard TH, Cornel LM, Unis AS, Lemire RJ. The teratogenicity of N (omega)-nitro-L-ariginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, in rats. Reprod Toxicol 1997; 11(5): 709-717   DOI   ScienceOn
4 Han RN, Babaei S, Robb M, Lee T, Ridsdale R, Ackerley C, Post M, Stewart DJ. Defective lung vascular development and fatal respiratory distress in endothelial NO synthase-deficient mice: a model of alveolar capillary dysplasia? Circ Res 2004; 94(8): 1115-1123   DOI   ScienceOn
5 Feng Q, Song W, Lu X, Hamilton JA, Lei M, Peng T, Yee SP. Development of heart failure and congenital septal defects in mice lacking endothelial nitric oxide synthase. Circulation 2002; 106 (7): 873-879   DOI   ScienceOn
6 Waggoner DJ, Bartnikas TB, Gitlin JD. The role of copper in neurodegenerative disease. Neurobiol Dis 1999; 6(4): 221-230   DOI   ScienceOn
7 Klevay LM. Cardiovascular disease from copper deficiency--a history. J Nutr 2000; 130(2S Suppl): 489S-492S   DOI
8 Keen CL, Hanna LA, Lanoue L, Uriu-Adams JY, Rucker RB, Clegg MS. Developmental consequences of trace mineral deficiencies in rodents: acute and long-term effects. J Nutr 2003; 133(5 Suppl 1): 1477S-1480S   DOI
9 Yang SJ, Uriu-Adams JY, Keen CL, Rucker RB, Lanoue L. Effects of copper deficiency on mouse yolk sac vasculature and expression of angiogenic mediators. Birth Defects Res B Dev Reprod Toxicol 2006; 77(5): 445-454   DOI   ScienceOn
10 Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 2000; 87(10): 840-844   DOI
11 Kelm M, Rath J. Endothelial dysfunction in human coronary circulation: relevance of the L-arginine-NO pathway. Basic Res Cardiol 2001; 96(2): 107-127   DOI   ScienceOn
12 Brown NA. Routine assessment of morphology and growth: scoring system and measurements of size. In: Copp AJ, Cockroft DL, editor. Postimplantation mammalian embryos: a practical pproach. Oxford:IRL Press at Oxford University Press; 1990. p.93-108
13 Hawk SN, Uriu-Hare JY, Daston GP, Jankowski MA, Kwik-Uribe C, Rucker RB, Keen CL. Rat embryos cultured under copperdeficient conditions develop abnormally and are characterized by an impaired oxidant defense system. Teratology 1998; 57: 310-320   DOI   ScienceOn
14 Chen HW, Jiang WS, Tzeng CR. Nitric oxide as a regulator in preimplantation embryo development and apoptosis. Fertil Steril 2001; 75(6): 1163-1171   DOI   ScienceOn
15 Menzies AS, Aszodi A, Williams SE, Pfeifer A, Wehman AM, Goh KL, Mason CA, Fassler R, Gertler FB. Mena and vasodilator-stimulated phosphoprotein are required for multiple actin-dependent processes that shape the vertebrate nervous system. J Neurosci 2004; 24(37): 8029-8038   DOI   ScienceOn
16 Shukovski L, Tsafriri A. The involvement of nitric oxide in the ovulatory process in the rat. Endocrinology 1994; 135(5): 2287-2290   DOI   ScienceOn
17 Ekerhovd E, Enskog A, Caidahl K, Klintland N, Nilsson L, Brannstrom M, Norstrom A. Plasma concentrations of nitrate during the menstrual cycle, ovarian stimulation and ovarian hyperstimulation syndrome. Hum Reprod 2001; 16(7): 1334-1339   DOI   ScienceOn
18 Sengoku K, Takuma N, Horikawa M, Tsuchiya K, Komori H. Sharifa D, Tamate K, Ishikaw M. Requirement of nitric oxide for murine oocyte maturation, embryo development, and trophoblast outgrowth in vitro. Mol Reprod Dev 2001; 58(3): 262-268   DOI   ScienceOn
19 Lanier LM, Gates MA, Witke W, Menzies AS, Wehman AM, Macklis JD, Kwiatkowski D, Soriano P, Gertler FB. Mena is required for neurulation and commissure formation. Neuron 1999; 22(2): 313-325   DOI   ScienceOn
20 Lynch SM, Frei B, Morrow JD, Roberts LJ 2nd, Xu A, Jackson T, Reyna R, Klevay LM, Vita JA, Keaney JF Jr. Vascular superoxide dismutase deficiency impairs endothelial vasodilator function through direct inactivation of nitric oxide and increased lipid peroxidation. Arterioscler Thromb Vasc Biol 1997; 17(11): 2975-2981   DOI
21 Keen CL, Uriu-Hare JY, Hawk SN, Jankowski MA, Daston GP, Kwik-Uribe CL, Rucker RB. Effect of copper deficiency on prenatal development and pregnancy outcome. Am J Clin Nutr 1998; 67(5 Suppl): 1003S-1011S   DOI
22 Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev 2007; 87(1): 315-424   DOI   ScienceOn
23 Schulz E, Tsilimingas N, Rinze R, Reiter B, Wendt M, Oelze M, Woelken-Weckmuller S, Walter U, Reichenspurner H, Meinertz T, Munzel T. Functional and biochemical analysis of endothelial (dys)function and NO/$_cGMP$ signaling in human blood vessels with and without nitroglycerin pretreatment. Circulation 2002; 105 (10): 1170-1175   DOI   ScienceOn
24 Aszodi A, Pfeifer A, Ahmad M, Glauner M, Zhou XH, Ny L, Andersson KE, Kehrel B, Offermanns S, Fassler R. The vasodilatorstimulated phosphoprotein (VASP) is involved in cGMP- and cAMP-mediated inhibition of agonist-induced platelet aggregation, but is dispensable for smooth muscle function. Embo J 1999; 18 (1): 37-48   DOI   ScienceOn
25 Oelze M, Mollnau H, Hoffmann N, Warnholtz A, Bodenschatz M, Smolenski A, Walter U, Skatchkov M, Meinertz T, Munzel T. Vasodilator-stimulated phosphoprotein serine 239 phosphorylation as a sensitive monitor of defective nitric oxide/$_cGMP$ signaling and endothelial dysfunction. Circ Res 2000; 87(11): 999-1005   DOI
26 Krumenacker JS, Murad F. NO-cGMP signaling in development and stem cells. Mol Genet Metab 2006; 87(4): 311-314   DOI   ScienceOn
27 Schuschke DA, Falcone JC, Saari JT, Fleming JT, Percival SS, Young SA, Pass JM, Miller FN. Endothelial cell calcium mobilization to acetylcholine is attenuated in copper-deficient rats. Endothelium 2000; 7(2): 83-92   DOI
28 Thippeswamy T, McKay JS, Quinn JP, Morris R. Nitric oxide, a biological double-faced janus--is this good or bad?. Histol Histopathol 2006; 21(4): 445-458
29 Zalba G, Beaumont FJ, San Jose G, Fortuno A, Fortuno MA, Diez J. Is the balance between nitric oxide and superoxide altered in spontaneously hypertensive rats with endothelial dysfunction? Nephrol Dial Transplant 2001; 16 Suppl 1: 2-5
30 Gouge RC, Marshburn P, Gordon BE, Nunley W, Huet-Hudson YM. Nitric oxide as a regulator of embryonic development. Biol Reprod 1998; 58(4): 875-879   DOI   ScienceOn
31 Ibarra-Alvarado C, Galle J, Melichar VO, Mameghani A, Schmidt HH. Phosphorylation of blood vessel vasodilator-stimulated phosphoprotein at serine 239 as a functional biochemical marker of endothelial nitric oxide/cyclic GMP signaling. Mol Pharmacol 2002; 61(2): 312-319   DOI   ScienceOn
32 Nath AK, Madri JA. The roles of nitric oxide in murine cardiovascular development. Dev Biol 2006; 292(1): 25-33   DOI   ScienceOn
33 Bitar MS, Wahid S, Mustafa S, Al-Saleh E, Dhaunsi GS, Al-Mulla F. Nitric oxide dynamics and endothelial dysfunction in type II model of genetic diabetes. Eur J Pharmacol 2005; 511(1): 53-64   DOI   ScienceOn
34 Schuschke DA, Saari JT, Miller FN. A role for dietary copper in nitric oxide-mediated vasodilation. Microcirculation 1995; 2(4):371-376   DOI   ScienceOn
35 Young SL, Evans K, Eu JP. Nitric oxide modulates branching morphogenesis in fetal rat lung explants. Am J Physiol Lung Cell Mol Physiol 2002; 282(3): 379-385   DOI
36 Scherrer-Crosbie M, Ullrich R, Bloch KD, Nakajima H, Nasseri B, Aretz HT, Lindsey ML, Vancon AC, Huang PL, Lee RT, Zapol WM, Picard MH. Endothelial nitric oxide synthase limits left ventricular remodeling after myocardial infarction in mice. Circulation 2001; 104(11): 1286-1291   DOI   ScienceOn
37 Penland JG, Prohaska JR. Abnormal motor function persists following recovery from perinatal copper deficiency in rats. J Nutr 2004; 134(8): 1984-1988   DOI
38 Hefler LA, Reyes CA, O'Brien WE, Gregg AR. Perinatal devel opment of endothelial nitric oxide synthase-deficient mice. Biol Reprod 2001; 64(2): 666-673   DOI   ScienceOn
39 Amirmansour C, Vallance P, Bogle RG, Tyrosine nitration in blood vessels occurs with increasing nitric oxide concentration. Br J Pharmacol 1999; 127(3): 788-794   DOI   ScienceOn
40 Jablonka-Shariff A, Basuray R, Olson LM. Inhibitors of nitric oxide synthase influence oocyte maturation in rats. J Soc Gynecol Investig 1999; 6(2): 95-101   DOI   ScienceOn
41 Fantel AG, Stamps LD, Tran TT, Mackler B, Person RE, Nekahi N. Role of free radicals in the limb teratogenicity of L-NAME (N(G)-nitro-(L)-arginine methyl ester): a new mechanistic model of vascular disruption. Teratology 1999; 60(3): 151-160   DOI   ScienceOn
42 Jablonka-Shariff A, Olson LM. The role of nitric oxide in oocyte meiotic maturation and ovulation: meiotic abnormalities of endothelial nitric oxide synthase knock-out mouse oocytes. Endocrinology 1998; 139(6): 2944-2954   DOI   ScienceOn
43 Beckers-Trapp ME, Lanoue L, Keen CL, Rucker RB, Uriu-Adams JY. Abnormal development and increased 3-nitrotyrosine in copper-deficient mouse embryos. Free Radic Biol Med 2006; 40(1): 35-44   DOI   ScienceOn