Division of Maternal Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Texas Health Science Center at Houston, Houston, TX.
Division of Maternal Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Texas Health Science Center at Houston, Houston, TX.
Am J Obstet Gynecol. 2019 Mar;220(3):279.e1-279.e9. doi: 10.1016/j.ajog.2018.11.1101. Epub 2018 Dec 3.
Inositols (INOs) supplementation during pregnancy, specifically the combination of myo-inositol (MI) and D-chiro-inositol (DCI), has been reported to improve vascular parameters in women with gestational diabetes mellitus. We demonstrated previously that offspring born to pregnant mice lacking the endothelial nitric oxide synthase (eNOS+/-) gene have hypertension (HTN) as adults and, when fed a high-fat diet (HFD), develop a metabolic syndrome (MS) phenotype.
Our aim was to evaluate whether INOs treatment in pregnancy complicated by MS improves the vascular and metabolic profile in mice offspring programmed in utero to develop HTN and MS.
Heterozygous eNOS+/- mice fed an HFD manifest a MS phenotype. Female eNOS+/- mice with MS were bred with a wild-type (WT) male. On gestational day 1, pregnant females were randomly allocated to receive either a mixture of INOs (MI/DCI: 7.2/0.18 mg/mL) or water as placebo until delivery. The female offspring obtained were genotyped and categorized as: WT (genetically normal, with eNOS gene) and eNOS+/- offspring (genetically modified, heterozygous for eNOS gene). Both offspring developed in an abnormal uterine environment due to maternal MS. At 9-10 weeks of age, the offspring underwent a glucose tolerance test (GTT) and systolic blood pressure (SBP) measurement. The mice were then sacrificed, and the carotid arteries were isolated for evaluation of vascular responses. Responses to phenylephrine (PE), in the presence and absence of a nonspecific nitric oxide inhibitor (N-nitro-L-arginine methyl ester [L-NAME]), the vasodilator acetylcholine (ACh), and sodium nitroprusside (SNP) were assessed.
The GTT showed lower glucose levels in both eNOS+/-INOs (P = .03) and WT-INOs (P = .05) offspring born to MS dams on INOs supplementation compared to offspring born to untreated dams. SBP was higher in eNOS+/- offspring compared to WT (169 ± 7 vs 142 ± 9 mm Hg, respectively, P = .04) and INOs treatment decreased SBP in WT-INOs (110 ± 10 mm Hg, P = .01) but not in eNOS+/-INOs offspring. Maximal (%Max) contractile response to PE was higher in eNOS+/- offspring born to MS dams and was decreased in those born to MS dams treated with INOs (%Max, eNOS+/-, 123 ± 7 vs eNOS+/-INOs, 82 ± 11 mm Hg, P = .007). No differences were seen in PE contractile responses in WT offspring born to MS dams treated or not treated with INOs (WT, 92 ± 4 vs WT-INOs, 75 ± 7). The L-NAME response was decreased in eNOS+/-INOs and WT-INOs offspring compared to untreated ones. The ACh vasorelaxation was impaired in eNOS+/- and WT offspring born to MS dams, and maternal INOs treatment improved offspring vascular relaxation in both offspring (P = .01 and P = .03, respectively). No differences were seen in response to SNP.
Inositols supplementation improved glucose tolerance, SBP, and vascular responses in adult eNOS+/- and WT offspring born to dams with MS. Interestingly, WT born to MS dams show an altered vascular profile similar to eNOS+/- offspring and exhibit an improved response to INOs treatment. Our findings suggest that the benefits of INOs treatment are more pronounced in offspring exposed to environmental factors in utero, and less likely in those due to genetic factors.
在妊娠期间补充肌醇（INOs），特别是肌醇（MI）和 D-手性肌醇（DCI）的组合，据报道可以改善患有妊娠糖尿病的女性的血管参数。我们之前已经证明，缺乏内皮型一氧化氮合酶（eNOS+/-）基因的怀孕小鼠所生的后代在成年时会患有高血压（HTN），并且如果给予高脂肪饮食（HFD），则会发展出代谢综合征（MS）表型。
我们的目的是评估在患有 MS 的妊娠期间进行 INOs 治疗是否可以改善在子宫内编程以发展为 HTN 和 MS 的小鼠后代的血管和代谢状况。
杂合子 eNOS+/- 小鼠喂食 HFD 会表现出 MS 表型。患有 MS 的雌性 eNOS+/- 小鼠与野生型（WT）雄性交配。在妊娠第 1 天，随机分配怀孕的雌性接受 INOs 混合物（MI/DCI：7.2/0.18 mg/mL）或水作为安慰剂，直至分娩。获得的雌性后代进行基因分型，并分为：WT（遗传正常，具有 eNOS 基因）和 eNOS+/- 后代（遗传修饰，杂合子 eNOS 基因）。由于母体 MS，这两种后代都在异常的子宫环境中发育。在 9-10 周龄时，对后代进行葡萄糖耐量试验（GTT）和收缩压（SBP）测量。然后处死小鼠，分离颈动脉评估血管反应。评估对苯肾上腺素（PE）的反应，包括存在和不存在非特异性一氧化氮抑制剂（N-硝基-L-精氨酸甲酯[L-NAME]）、血管扩张剂乙酰胆碱（ACh）和硝普钠（SNP）。
GTT 显示，与未接受治疗的 MS 母鼠所生的后代相比，来自 MS 母鼠且接受 INOs 治疗的 eNOS+/- 和 WT 后代的血糖水平更低（P =.03 和 P =.05）。与 WT 相比，eNOS+/- 后代的 SBP 更高（分别为 169 ± 7 与 142 ± 9 mmHg，P =.04），而 INOs 治疗降低了 WT-INOs 后代的 SBP（110 ± 10 mmHg，P =.01），但不降低 eNOS+/-INOs 后代的 SBP。PE 最大收缩反应（%Max）在来自 MS 母鼠的 eNOS+/- 后代中更高，并且在来自接受 INOs 治疗的 MS 母鼠的后代中降低（%Max，eNOS+/-，123 ± 7 与 eNOS+/-INOs，82 ± 11 mmHg，P =.007）。来自 MS 母鼠且接受或未接受 INOs 治疗的 WT 后代的 PE 收缩反应没有差异（WT，92 ± 4 与 WT-INOs，75 ± 7）。与未接受治疗的后代相比，eNOS+/-INOs 和 WT-INOs 后代的 L-NAME 反应降低。来自 MS 母鼠的 eNOS+/- 和 WT 后代的 ACh 血管舒张功能受损，而母体 INOs 治疗改善了两种后代的血管舒张功能（P =.01 和 P =.03）。SNP 反应没有差异。
肌醇补充剂改善了患有 MS 的母鼠所生 eNOS+/- 和 WT 后代的葡萄糖耐量、SBP 和血管反应。有趣的是，来自 MS 母鼠的 WT 后代表现出类似于 eNOS+/- 后代的改变的血管特征，并且对 INOs 治疗有改善的反应。我们的研究结果表明，INOs 治疗的益处在暴露于子宫内环境因素的后代中更为明显，而在遗传因素导致的后代中则不太可能。
