Academic Unit of Human Development and Health, Faculty of Medicine, University of Southampton, Hampshire, United Kingdom.
PLoS One. 2012;7(4):e34492. doi: 10.1371/journal.pone.0034492. Epub 2012 Apr 3.
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 either 18:2n-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.
在发育过程中的营养会影响未来患心血管疾病的风险。相对而言，人们对于母亲饮食中的脂肪量和类型是否会影响后代的血管功能知之甚少。为了研究这个问题，研究人员给怀孕和哺乳期的老鼠喂食富含 18:2n-6、反式脂肪酸、饱和脂肪酸或鱼油的 7%（w/w）或 21%（w/w）脂肪。它们的后代从断奶开始到第 77 天喂食 4%（w/w）的大豆油。母鼠饮食中脂肪的类型和数量改变了后代主动脉和肠系膜动脉中乙酰胆碱（ACh）介导的血管舒张反应，这取决于性别。母鼠饮食中脂肪的数量而不是类型改变了这些动脉中苯肾上腺素（Pe）诱导的血管收缩。母鼠 21%脂肪饮食降低了后代主动脉中 20:4n-6 的浓度。我们研究了 Δ6 和 Δ5 去饱和酶的作用，结果表明，在主动脉和肠系膜动脉中抑制它们的活性会减少血管收缩，但不会减少血管舒张，并减少特定的促收缩类二十烷酸的合成。去除主动脉内皮不会改变抑制 Δ6 和 Δ5 去饱和酶对 Pe 介导的血管收缩的作用。因此，动脉平滑肌中 20:4n-6 的从头合成似乎对 Pe 介导的血管收缩很重要。接下来，我们研究了编码这些去饱和酶的基因，发现母鼠 21%脂肪降低了后代主动脉中 Fads2 的 mRNA 表达，并增加了 Fads1，表明 20:4n-6 生物合成失调。Fads2 转录起始位点 5'端的 CpG-394 bp 位点的甲基化预测了其表达。在母鼠喂食 21%脂肪的后代中，该基因座发生了过度甲基化。主动脉用 Pe 处理 10 分钟增加了 Fads2，但没有增加 Fads1 的 mRNA 表达（76%；P<0.05）。这表明 Fads2 可能是 Pe 作用于主动脉后即时早期基因。因此，母鼠饮食中的脂肪量和类型都会通过调节动脉多不饱和脂肪酸生物合成的表观遗传过程，引起后代血管张力的调节改变，表现为血管舒张的差异效应，以及血管收缩的持续变化。
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