Longo Monica, Refuerzo Jerrie S, Mann Lovepreet, Leon Mateo, Moussa Hind N, Sibai Baha M, Blackwell Sean C
Division of Maternal Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, McGovern Medical School at The University of Texas Health Science Center at Houston, Texas, USA.
Am J Hypertens. 2016 Dec 1;29(12):1366-1373. doi: 10.1093/ajh/hpw088.
We previously reported that offspring heterozygous mice partially lacking endothelial nitric oxide synthase (eNOS) gene, and born to hypertensive eNOS-/- Knockout mother, are hypertensive. We hypothesized that those offspring when placed on high-fat diet (HFD) will undergo altered metabolic programming increasing their risk for developing metabolic syndrome.
eNOS-/-KO and wild-type mice (eNOS+/+WT) were cross-bred to produce heterozygous offspring: maternal heterozygous (Mat, eNOS-/+), born from hypertensive eNOS-/-KO mothers; and paternal heterozygous (Pat, eNOS-/+), born from normotensive WT mothers. Mat, eNOS-/+ and Pat, eNOS-/+ female were allocated to HFD or control diet (CD) until 8 weeks of age. Then a metabolic profile was obtained: weight, glucose/insulin tolerance test (GTT, ITT), systolic blood pressure (SBP), serum fasting levels of insulin, adiponectin, leptin, and a lipid panel.
Weight was not different between all offspring within each diet. GTT curve was higher in Mat, eNOS-/+ vs. Pat, eNOS-/+ offspring on both diet (P < 0.001). In ITT, glucose level at 15 minutes was higher in Mat, eNOS-/+ on HFD. Insulin level was increased in Mat, eNOS-/+ vs. Pat, eNOS-/+ on either diet. SBP was elevated in Mat, eNOS-/+ vs. Pat, eNOS-/+ on CD and was further raised in Mat, eNOS-/+ offspring on HFD (P < 0.001). No other differences were seen except for lower high-density lipoprotein levels in Mat, eNOS-/+ fed HFD (P < 0.003).
Mat, eNOS-/+ offspring exposed in utero to maternal hypertension and fed HFD postnatally have increased susceptibility for metabolic abnormalities. Thus, maternal HTN is a risk factor for altered fetal metabolic programming.
我们之前报道过，部分缺乏内皮型一氧化氮合酶（eNOS）基因的杂合子后代，其母亲为高血压eNOS-/-基因敲除小鼠，这些后代会出现高血压。我们推测，这些后代在食用高脂饮食（HFD）时，会经历代谢编程改变，增加患代谢综合征的风险。
将eNOS-/-基因敲除小鼠和野生型小鼠（eNOS+/+野生型）杂交，产生杂合子后代：母本杂合子（Mat，eNOS-/+），由高血压eNOS-/-基因敲除母本所生；父本杂合子（Pat，eNOS-/+），由血压正常的野生型母本所生。将Mat、eNOS-/+和Pat、eNOS-/+雌性小鼠分配至高脂饮食或对照饮食（CD）组，直至8周龄。然后获取代谢概况：体重、葡萄糖/胰岛素耐量试验（GTT、ITT）、收缩压（SBP）、血清空腹胰岛素水平、脂联素、瘦素以及血脂谱。
每种饮食组内所有后代的体重无差异。在两种饮食条件下，Mat、eNOS-/+后代的GTT曲线均高于Pat、eNOS-/+后代（P < 0.001）。在ITT中，高脂饮食组的Mat、eNOS-/+小鼠在15分钟时的血糖水平更高。在任何一种饮食条件下，Mat、eNOS-/+小鼠的胰岛素水平均高于Pat、eNOS-/+小鼠。对照饮食组中，Mat、eNOS-/+小鼠的SBP高于Pat、eNOS-/+小鼠，高脂饮食组的Mat、eNOS-/+后代的SBP进一步升高（P < 0.001）。除了高脂饮食喂养的Mat、eNOS-/+小鼠的高密度脂蛋白水平较低外（P < 0.003），未观察到其他差异。
在子宫内暴露于母本高血压且出生后食用高脂饮食的Mat、eNOS-/+后代，对代谢异常的易感性增加。因此，母本高血压是胎儿代谢编程改变的一个危险因素。
