Departments of Obstetrics, Gynecology, Reproductive Sciences and Physiology, University of Maryland School of Medicine , Baltimore, MD, USA.
Department of Kinesiology, University of Maryland School of Public Health, College Park, MD, USA.
Endocrinology. 2022 May 1;163(5). doi: 10.1210/endocr/bqac037.
We have shown that normal weight offspring born to estrogen-deprived baboons exhibited insulin resistance, although liver and adipose function and insulin receptor and glucose transporter expression were unaltered. The blood microvessels have an important role in insulin action by delivering insulin and glucose to target cells. Although little is known about the regulation of microvessel development during fetal life, estrogen promotes capillary proliferation and vascular function in the adult. Therefore, we tested the hypothesis that estrogen promotes fetal microvessel development and thus vascular function and insulin sensitivity in offspring. Capillary/myofiber ratio was decreased 75% (P < 0.05) in skeletal muscle, a major insulin target tissue, of fetal baboons in which estradiol levels were depleted by administration of aromatase inhibitor letrozole. This was sustained after birth, resulting in a 50% reduction (P < 0.01) in microvessel expansion; 65% decrease (P < 0.01) in arterial flow-mediated dilation, indicative of vascular endothelial dysfunction; and 35% increase (P < 0.01) in blood pressure in offspring from estrogen-deprived baboons, changes prevented by letrozole and estradiol administration. Along with vascular dysfunction, peak insulin and glucose levels during a glucose tolerance test were greater (P < 0.05 to P < 0.01) and the homeostasis model of insulin resistance 2-fold higher (P < 0.01) in offspring of letrozole-treated than untreated animals, indicative of insulin resistance. This study makes the novel discovery that estrogen promotes microvascularization in the fetus and thus normal vascular development and function required for eliciting insulin sensitivity in offspring and that placental hormonal secretions, independent from improper fetal growth, are an important determinant of risk of developing insulin resistance.
我们已经表明，出生于去雌激素狒狒的正常体重后代表现出胰岛素抵抗，尽管肝脏和脂肪组织功能以及胰岛素受体和葡萄糖转运体的表达没有改变。血液微血管通过向靶细胞输送胰岛素和葡萄糖在胰岛素作用中起重要作用。尽管关于胎儿期微血管发育的调节知之甚少，但雌激素可促进成年毛细血管增殖和血管功能。因此，我们检验了以下假说：雌激素促进胎儿微血管发育，从而促进后代的血管功能和胰岛素敏感性。在接受芳香酶抑制剂来曲唑治疗以耗尽雌二醇水平的胎儿狒狒中，骨骼肌（胰岛素的主要靶组织）中的毛细血管/肌纤维比降低了 75%（P<0.05）。这种情况在出生后仍持续存在，导致微血管扩张减少 50%（P<0.01）；动脉血流介导的扩张减少 65%（P<0.01），表明血管内皮功能障碍；以及去雌激素狒狒后代的血压增加 35%（P<0.01），这些变化可通过来曲唑和雌二醇给药来预防。伴随着血管功能障碍，葡萄糖耐量试验期间的胰岛素和葡萄糖峰值水平在来曲唑处理的而非未处理的动物后代中更高（P<0.05 至 P<0.01），并且胰岛素抵抗的稳态模型评估 2 倍更高（P<0.01），提示胰岛素抵抗。这项研究首次发现，雌激素可促进胎儿微血管生成，从而促进正常的血管发育和功能，以引发后代的胰岛素敏感性，并且胎盘激素分泌（与胎儿生长不当无关）是发展为胰岛素抵抗的重要决定因素。
