Cellular and Molecular Physiology Laboratory (CMPL), Department of Obstetrics, Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, 8330024, Chile.
Cellular and Molecular Physiology Laboratory (CMPL), Department of Obstetrics, Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, 8330024, Chile; FH JOANNEUM Gesellschaft MbH University of Applied Sciences, Institute of Biomedical Science, Eggenberger Allee 13, 8020, Graz, Austria.
Placenta. 2019 Oct;86:35-44. doi: 10.1016/j.placenta.2019.07.007. Epub 2019 Jul 16.
Pregestational maternal obesity (PGMO) associates with foetoplacental vascular endothelial dysfunction and higher risk for insulin resistance in the neonate. We characterised the PGMO consequences on the insulin response of the human foetoplacental vasculature.
Umbilical veins were from pregnancies where the mother was with PGMO (body mass index 30-42.3 kg/m, n = 33) or normal pregestational weight (PGMN) (body mass index 19.5-24.4 kg/m, n = 21) with total gestational weight gain within the physiological range. Umbilical vein ring segments were mounted in a myograph for isometric force measurements. Primary cultures of human umbilical vein endothelial cells were used in passage 3. Vessel rings and cells were exposed to 1 nmol/L insulin (20 min) in the absence or presence of 100 μmol/L N-nitro-l-arginine methyl ester (inhibitor of nitric oxide synthase, NOS).
Vessel rings from PGMO showed reduced nitric oxide synthase-activity dependent dilation to insulin or calcitonin-gene related peptide compared with PGMN. PGMO associated with higher inhibitor phosphorylation of the insulin receptor substrate 1 (IRS-1) and lower activator phosphorylation of protein kinase B/Akt (Akt). Cells from PGMO also showed lower nitric oxide level and reduced activator serine but increased inhibitor threonine phosphorylation of endothelial nitric oxide synthase (eNOS) and saturable transport of l-arginine. HUVECs from PGMO were not responsive to insulin.
The lack of response to insulin by the foetoplacental endothelium may result from reduced IRS-1/Akt/eNOS signalling in PGMO. These findings may result in higher risk of insulin resistance in neonates to PGMO pregnancies.
孕前母体肥胖（PGMO）与胎儿胎盘血管内皮功能障碍和新生儿胰岛素抵抗风险增加有关。我们研究了 PGMO 对人胎胎盘血管胰岛素反应的影响。
从母亲患有 PGMO（体重指数 30-42.3kg/m²，n=33）或正常孕前体重（PGMN）（体重指数 19.5-24.4kg/m²，n=21）且总孕期体重增加在生理范围内的妊娠中获得脐静脉。将脐静脉环段安装在肌动描记器上进行等长力测量。使用第 3 代人脐静脉内皮细胞进行原代培养。血管环和细胞在不存在或存在 100µmol/L N-硝基-L-精氨酸甲酯（一氧化氮合酶抑制剂，NOS）的情况下，暴露于 1nmol/L 胰岛素（20 分钟）。
与 PGMN 相比，PGMO 血管环对胰岛素或降钙素基因相关肽的一氧化氮合酶依赖性扩张减少。PGMO 与胰岛素受体底物 1（IRS-1）的抑制剂磷酸化升高和蛋白激酶 B/Akt（Akt）的激活剂磷酸化降低相关。PGMO 细胞的一氧化氮水平也较低，内皮型一氧化氮合酶（eNOS）的激活剂丝氨酸减少和抑制剂苏氨酸增加，并且 l-精氨酸的可饱和转运减少。来自 PGMO 的 HUVEC 对胰岛素无反应。
PGMO 中 IRS-1/Akt/eNOS 信号转导减少可能导致胎胎盘内皮对胰岛素无反应。这些发现可能导致 PGMO 妊娠的新生儿胰岛素抵抗风险增加。
