Nutrition during development affects risk of future cardiovascular disease. Relatively little is known about whether the amount and type of fat in the maternal diet affect vascular function in the offspring. To investigate this, pregnant and lactating rats were fed either 7%(w/w) or 21%(w/w) fat enriched in either18:2n-6, trans fatty acids, saturated fatty acids, or fish oil. Their offspring were fed 4%(w/w) soybean oil from weaning until day 77. Type and amount of maternal dietary fat altered acetylcholine (ACh)-mediated vaso-relaxation in offspring aortae and mesenteric arteries, contingent on sex. Amount, but not type, of maternal dietary fat altered phenylephrine (Pe)-induced vasoconstriction in these arteries. Maternal 21% fat diet decreased 20:4n-6 concentration in offspring aortae. We investigated the role of Δ6 and Δ5 desaturases, showing that their inhibition in aortae and mesenteric arteries reduced vasoconstriction, but not vaso-relaxation, and the synthesis of specific pro-constriction eicosanoids. Removal of the aortic endothelium did not alter the effect of inhibition of Δ6 and Δ5 desaturases on Pe-mediated vasoconstriction. Thus arterial smooth muscle 20:4n-6 biosynthesis de novo appears to be important for Pe-mediated vasoconstriction. Next we studied genes encoding these desaturases, finding that maternal 21% fat reduced Fads2 mRNA expression and increased Fads1 in offspring aortae, indicating dysregulation of 20:4n-6 biosynthesis. Methylation at CpG ？394 bp 5′ to the Fads2 transcription start site predicted its expression. This locus was hypermethylated in offspring of dams fed 21% fat. Pe treatment of aortae for 10 minutes increased Fads2, but not Fads1, mRNA expression (76%; P<0.05). This suggests that Fads2 may be an immediate early gene in the response of aortae to Pe. Thus both amount and type of maternal dietary fat induce altered regulation of vascular tone in offspring though differential effects on vaso-relaxation, and persistent changes in vasoconstriction via epigenetic processes controlling arterial polyunsaturated fatty acid biosynthesis.
References
[1]
Giannotti G, Landmesser U (2007) Endothelial dysfunction as an early sign of atherosclerosis. Herz 32: 568–572.
[2]
Schwartz SM (1980) Role of endothelial integrity in atherosclerosis. Artery 8: 305–314.
[3]
Feletou M, Huang Y, Vanhoutte PM (2010) Vasoconstrictor prostanoids. Pflugers Arch 459: 941–950.
[4]
Hunter JE, Zhang J, Kris-Etherton PM (2010) Cardiovascular disease risk of dietary stearic acid compared with trans, other saturated, and unsaturated fatty acids: a systematic review. Am J Clin Nutr 91: 46–63.
[5]
Psota TL, Gebauer SK, Kris-Etherton P (2006) Dietary omega-3 fatty acid intake and cardiovascular risk. Am J Cardiolo 98: 3I–18I.
[6]
Burdge GC, Calder PC (2006) Dietary alpha-linolenic acid and health-related outcomes: a metabolic perspective. Nutr Res Rev 19: 26–52.
[7]
Czernichow S, Thomas D, Bruckert E (2010) n-6 Fatty acids and cardiovascular health: a review of the evidence for dietary intake recommendations. Br J Nutr 104: 788–796.
[8]
Voss AC, Sprecher H (1988) Regulation of the metabolism of linoleic acid to arachidonic acid in rat hepatocytes. Lipids 23: 660–665.
[9]
Das UN (2007) A defect in the activity of Delta6 and Delta5 desaturases may be a factor in the initiation and progression of atherosclerosis. Prostaglandins Leukot Essent Fatty Acids 76: 251–268.
[10]
Simopoulos AP (2010) Genetic variants in the metabolism of omega-6 and omega-3 fatty acids: their role in the determination of nutritional requirements and chronic disease risk. Exp Biol Med (Maywood) 235: 785–795.
[11]
Ringseis R, Eder K (2010) Fatty acids and signalling in endothelial cells. Prostaglandins Leukot Essent Fatty Acids 82: 189–198.
[12]
Saravanan P, Davidson NC, Schmidt EB, Calder PC (2010) Cardiovascular effects of marine omega-3 fatty acids. Lancet 376: 540–550.
[13]
Rosenthal MD, Whitehurst MC (1983) Fatty acyl delta 6 desaturation activity of cultured human endothelial cells. Modulation by fetal bovine serum. Biochim Biophys Acta 750: 490–496.
[14]
Harmon SD, Kaduce TL, Manuel TD, Spector AA (2003) Effect of the delta6-desaturase inhibitor SC-26196 on PUFA metabolism in human cells. Lipids 38: 469–476.
[15]
Gluckman PD, Hanson MA, Cooper C, Thornburg KL (2008) Effect of in utero and early-life conditions on adult health and disease. N Engl J Med 359: 61–73.
[16]
Khan IY, Taylor PD, Dekou V, Seed PT, Lakasing L, et al. (2003) Gender-linked hypertension in offspring of lard-fed pregnant rats. Hypertension 41: 168–175.
[17]
Taylor PD, Khan IY, Hanson MA, Poston L (2004) Impaired EDHF-mediated vasodilatation in adult offspring of rats exposed to a fat-rich diet in pregnancy. J Physiol 558: 943–951.
[18]
Armitage JA, Lakasing L, Taylor PD, Balachandran AA, Jensen RI, et al. (2005) Developmental programming of aortic and renal structure in offspring of rats fed fat-rich diets in pregnancy. J Physiol 565: 171–184.
[19]
Armitage JA, Ishibashi A, Balachandran AA, Jensen RI, Poston L, et al. (2007) Programmed aortic dysfunction and reduced Na+,K+-ATPase activity present in first generation offspring of lard-fed rats does not persist to the second generation. Exp Physiol 92: 583–589.
[20]
Weisinger HS, Armitage JA, Sinclair AJ, Vingrys AJ, Burns PL, et al. (2001) Perinatal omega-3 fatty acid deficiency affects blood pressure later in life. Nat Med 7: 258–259.
[21]
Lillycrop KA, Phillips ES, Jackson AA, Hanson MA, Burdge GC (2005) Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr 135: 1382–1386.
[22]
Gluckman PD, Lillycrop KA, Vickers MH, Pleasants AB, Phillips ES, et al. (2007) Metabolic plasticity during mammalian development is directionally dependent on early nutritional status. Proc Natl Acad Sci USA 104: 12796–12800.
[23]
Wolff GL, Kodell RL, Moore SR, Cooney CA (1998) Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice. FASEB J 12: 949–957.
[24]
Plagemann A, Harder T, Brunn M, Harder A, Roepke K, et al. (2009) Hypothalamic proopiomelanocortin promoter methylation becomes altered by early overfeeding: an epigenetic model of obesity and the metabolic syndrome. J Physiol 587: 4963–4976.
[25]
Reeves PG (1997) Components of the AIN-93 diets as improvements in the AIN-76A diet. J Nutr 127: 838S–841S.
[26]
Torrens C, Hanson MA, Gluckman PD, Vickers MH (2009) Maternal undernutrition leads to endothelial dysfunction in adult male rat offspring independent of postnatal diet. Br J Nutr 101: 27–33.
[27]
Hansen-Petrik MB, McEntee MF, Johnson BT, Obukowicz MG, Masferrer J, et al. (2002) Selective inhibition of Delta-6 desaturase impedes intestinal tumorigenesis. Cancer Lett 175: 157–163.
[28]
Shimizu S, Akimoto K, Shinmen Y, Kawashima H, Sugano M, et al. (1991) Sesamin is a potent and specific inhibitor of delta 5 desaturase in polyunsaturated fatty acid biosynthesis. Lipids 26: 512–516.
[29]
Hilgers RH, De Mey JG (2009) Myoendothelial coupling in the mesenteric arterial bed; segmental differences and interplay between nitric oxide and endothelin-1. Br J Pharmacol 156: 1239–1247.
[30]
Burdge GC, Wright P, Jones AE, Wootton SA (2000) A method for separation of phosphatidylcholine, triacylglycerol, non-esterified fatty acids and cholesterol esters from plasma by solid-phase extraction. Br J Nutr 84: 781–787.
[31]
Folch J, Lees M, Sloane-Stanley GH (1957) A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 226: 497–509.
[32]
Burdge GC, Lillycrop KA, Phillips ES, Slater-Jefferies JL, Jackson AA, et al. (2009) Folic Acid Supplementation during the Juvenile-Pubertal Period in Rats Modifies the Phenotype and Epigenotype Induced by Prenatal Nutrition. J Nutr 139: 1054–1060.
[33]
Lillycrop KA, Slater-Jefferies JL, Hanson MA, Godfrey KM, Jackson AA, et al. (2007) Induction of altered epigenetic regulation of the hepatic glucocorticoid receptor in the offspring of rats fed a protein-restricted diet during pregnancy suggests that reduced DNA methyltransferase-1 expression is involved in impaired DNA methylation and changes in histone modifications. Br J Nutr 97: 1064–1073.
[34]
Bustin SA (2000) Absolute quantification of mRNA using real-time reverse transcription polymerase chain reaction assays. J Mol Endocrinol 25: 169–193.
[35]
Lillycrop KA, Phillips ES, Torrens C, Hanson MA, Jackson AA, et al. (2008) Feeding pregnant rats a protein-restricted diet persistently alters the methylation of specific cytosines in the hepatic PPARalpha promoter of the offspring. Br J Nutr 100: 278–282.
[36]
Harris RG, White E, Phillips ES, Lillycrop KA (2002) The expression of the developmentally regulated proto-oncogene Pax-3 is modulated by N-Myc. J Biol Chem 277: 34815–34825.
[37]
Masoodi M, Mir AA, Petasis NA, Serhan CN, Nicolaou A (2008) Simultaneous lipidomic analysis of three families of bioactive lipid mediators leukotrienes, resolvins, protectins and related hydroxy-fatty acids by liquid chromatography/electrospray ionisation tandem mass spectrometry. Rapid Commun Mass Spectrom 22: 75–83.
[38]
Masoodi M, Eiden M, Koulman A, Spaner D, Volmer DA (2010) Comprehensive lipidomics analysis of bioactive lipids in complex regulatory networks. Anal Chem 82: 8176–8185.
[39]
Antoniades C, Mussa S, Shirodaria C, Lee J, Diesch J, et al. (2009) Relation of preoperative radial artery flow-mediated dilatation to nitric oxide bioavailability in radial artery grafts used in off-pump coronary artery bypass grafting. Am J Cardiol 103: 216–220.
[40]
Virdis A, Ghiadoni L, Giannarelli C, Taddei S (2010) Endothelial dysfunction and vascular disease in later life. Maturitas 67: 20–24.
[41]
Torrens C, Brawley L, Anthony FW, Dance CS, Dunn R, et al. (2006) Folate supplementation during pregnancy improves offspring cardiovascular dysfunction induced by protein restriction. Hypertension 47: 982–987.
[42]
Chadha PS, Haddock RE, Howitt L, Morris MJ, Murphy TV, et al. (2010) Obesity up-regulates intermediate conductance calcium-activated potassium channels and myoendothelial gap junctions to maintain endothelial vasodilator function. J Pharmacol Exp Ther 335: 284–293.
[43]
Couloubaly S, Delomenie C, Rousseau D, Paul JL, Grynberg A, et al. (2007) Fatty acid incorporation in endothelial cells and effects on endothelial nitric oxide synthase. Eur J Clin Invest 37: 692–699.
[44]
Goligorsky MS, Li H, Brodsky S, Chen J (2002) Relationships between caveolae and eNOS: everything in proximity and the proximity of everything. American Journal of Physiology: Renal Physiol 283: F1–F10.
[45]
Ghosh P, Bitsanis D, Ghebremeskel K, Crawford MA, Poston L (2001) Abnormal aortic fatty acid composition and small artery function in offspring of rats fed a high fat diet in pregnancy. J Physiol 533: 815–822.
[46]
Six DA, Dennis EA (2000) The expanding superfamily of phospholipase A(2) enzymes: classification and characterization. Biochim Biophys Acta 1488: 1–19.
[47]
Smith WL, DeWitt DL, Garavito RM (2000) Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem 69: 145–182.
[48]
Wise H, Wong YH, Jones RL (2002) Prostanoid signal integration and cross talk. Neurosignals 11: 20–28.
[49]
Delton-Vandenbroucke I, Grammas P, Anderson RE (1997) Polyunsaturated fatty acid metabolism in retinal and cerebral microvascular endothelial cells. J Lipid Res 38: 147–159.
[50]
Mozaffarian D (2006) Trans fatty acids - effects on systemic inflammation and endothelial function. Atheroscler Suppl 7: 29–32.
[51]
Pettersen J, Opstvedt J (1992) trans fatty acids. 5. Fatty acid composition of lipids of the brain and other organs in suckling piglets. Lipids 27: 761–769.
[52]
Innis SM, King DJ (1999) trans Fatty acids in human milk are inversely associated with concentrations of essential all-cis n-6 and n-3 fatty acids and determine trans, but not n-6 and n-3, fatty acids in plasma lipids of breast-fed infants. Am J Clin Nutr 70: 383–390.
[53]
Koletzko B (1992) Trans fatty acids may impair biosynthesis of long-chain polyunsaturates and growth in man. Acta Paediatr 81: 302–306.
[54]
Decsi T, Koletzko B (1995) Do trans fatty acids impair linoleic acid metabolism in children? Ann Nutr Metab 39: 36–41.
[55]
De Schrijver R, Privett OS (1982) Interrelationship between dietary trans Fatty acids and the 6- and 9-desaturases in the rat. Lipids 17: 27–34.
[56]
Chiu HC, Kovacs A, Ford DA, Hsu FF, Garcia R, et al. (2001) A novel mouse model of lipotoxic cardiomyopathy. J Clin Invest 107: 813–822.
[57]
Cho HP, Nakamura M, Clarke SD (1999) Cloning, expression, and fatty acid regulation of the human delta-5 desaturase. J Biol Chem 274: 37335–37339.
[58]
Chapkin RS, Somers SD, Erickson KL (1988) Inability of murine peritoneal macrophages to convert linoleic acid into arachidonic acid. Evidence of chain elongation. J Immunol 140: 2350–2355.
[59]
Anel A, Naval J, Gonzalez B, Torres JM, Mishal Z, et al. (1990) Fatty acid metabolism in human lymphocytes. I. Time-course changes in fatty acid composition and membrane fluidity during blastic transformation of peripheral blood lymphocytes. Biochim Biophys Acta 1044: 323–331.
[60]
Kwak JH, Paik JK, Kim OY, Jang Y, Lee SH, et al. (2011) FADS gene polymorphisms in Koreans: association with omega6 polyunsaturated fatty acids in serum phospholipids, lipid peroxides, and coronary artery disease. Atherosclerosis 214: 94–100.
[61]
Martinelli N, Girelli D, Malerba G, Guarini P, Illig T, et al. (2008) FADS genotypes and desaturase activity estimated by the ratio of arachidonic acid to linoleic acid are associated with inflammation and coronary artery disease. Am J Clin Nutr 88: 941–949.
[62]
Devlin AM, Singh R, Wade RE, Innis SM, Bottiglieri T, et al. (2007) Hypermethylation of Fads2 and altered hepatic fatty acid and phospholipid metabolism in mice with hyperhomocysteinemia. J Biol Chem 282: 37082–37090.
[63]
Babu GJ, Lalli MJ, Sussman MA, Sadoshima J, Periasamy M (2000) Phosphorylation of elk-1 by MEK/ERK pathway is necessary for c-fos gene activation during cardiac myocyte hypertrophy. J Mol Cell Cardiol 32: 1447–1457.
[64]
Lattka E, Eggers S, Moeller G, Heim K, Weber M, et al. (2010) A common FADS2 promoter polymorphism increases promoter activity and facilitates binding of transcription factor ELK1. J Lipid Res 51: 182–191.
