Estrogen Promotes Microvascularization in the Fetus and Thus Vascular Function and Insulin Sensitivity in Offspring

Abstract

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.

Keywords: estrogen; insulin resistance; microvessels; primate.