Intrauterine Stress Disrupts the Early Postnatal Maturation of Arterial Endothelium

The occurrence of cardiovascular disease in adults can be influenced or programmed by events that occurred in utero. This programming is thought to reflect intrauterine stress, including suboptimal delivery of nutrients to the growing fetus. Indeed, preclinical models of intrauterine growth restriction (IUGR) have confirmed pathological vascular changes, including endothelial vasodilator dysfunction, in adult offspring. The normal protective function of arterial endothelium, including NO‐mediated dilatation, is initiated in the immediate postnatal period and appears to be dependent on increased engagement and signaling of VE‐cadherin at Adherens Junctions ( Flavahan S et al, 2013, Am J Physiol Heart Circ Physiol. 305(3):H321–9 ). Indeed, newborn endothelial cells have a highly unusual phenotype, resembling dysfunctional endothelial cells that contribute to the development of vascular disease. The aim of the present study was to determine whether intrauterine stress might negatively impact this important maturation in endothelial function. Two established mouse models of IUGR were studied: the maternal low protein model, whereby dams are fed a low protein diet throughout pregnancy, and the endothelial NO synthase heterozygote model (eNOS +/− ), whereby the maternal eNOS −/− : paternal wild type matching causes intrauterine stress and the paternal eNOS −/− : maternal wild type combination serves as a control. Carotid arteries were isolated from newborn (postnatal day 1, P1), and neonatal mice (up to P21) and mounted in pressure myographs at a constant transmural pressure of 20 mmHg (mean blood pressure for a P1 mouse). In control arteries, from P1 to P21, there was a significant time‐dependent increase in NO‐mediated dilatation to the endothelial agonist acetylcholine, whereas the NO donor DEA‐NONOate caused similar dilatation in P1 through P21 arteries. The time‐dependent increase in endothelium‐dependent dilatation to acetylcholine was significantly impaired in neonates exposed to intrauterine stress. In control mice, this neonatal period was associated with a significant time‐dependent increase in the width and complexity of endothelial Adherens Junctions, determined by immunofluorescent labeling and LSM analysis of VE‐cadherin. This increase in VE‐cadherin localization at Adherens Junctions was significantly impaired in neonates exposed to intrauterine stress. In control mice, neonatal maturation of endothelial dilatation was inhibited by a function‐blocking antibody to VE‐cadherin, which inhibits VE‐cadherin engagement and disrupts endothelial Adherens Junctions. After intrauterine stress, the residual response to acetylcholine was not significantly affected by the function‐blocking antibody. A control antibody had no significant effects. The results indicate that intrauterine stress impairs the maturation of endothelium‐dependent dilatation in neonatal arteries and that this likely reflects impaired engagement and signaling of VE‐cadherin at Adherens Junctions. Delayed endothelial maturation might contribute to subsequent development of vascular disease in these offspring. Support or Funding Information NIH R01 HD078639