The concept that adult disease can be influenced by events occurring in utero is based on epidemiological studies demonstrating that infants born 'small for gestational age'(SGA) are at increased risk of developing cardiovascular and metabolic diseases. The theory is supported by animal studies demonstrating that intrauterine growth restriction (IUGR) causes cardiovascular and metabolic disorders. Cellular mechanisms responsible for this phenomenon have not yet been identified. Most IUGR studies have focused on adult consequences of the insult. However, this approach is complicated by indirect effects exerted by the disease processes, which are known to negatively impact vascular function. We have therefore focused on the immediate postnatal period, prior to development of these diseases. The immediate postnatal period is associated with remarkable changes in the structure and function of the endothelium and arterial wall. We demonstrate that the endothelium lining newborn arteries is highly unusual, possessing functional, morphological and signaling characteristics reminiscent of dysfunctional endothelial cells. These include prominent actin stress fibers, poorly organized Adherens Junctions (AJs), impaired eNOS and NO dilator activity, and powerful endothelin-mediated constriction. In the immediate postnatal period, endothelial cells rapidly mature into protective endothelium displaying a cortical actin network, highly-organized AJs, eNOS signaling and exuberant NO activity, and a complete lack of endothelin activity. Endothelial maturation appears to reflect increased signaling at AJs, resulting in a change in endothelial signaling from predominantly Rho/ROCK signaling in newborn endothelium to PI3K/Akt signaling in maturing endothelium. This postnatal maturation process was disrupted in two mouse models of IUGR, with endothelial cells retaining newborn characteristics, including diminished AJ organization and impaired NO activity, present in maturing neonatal arteries. Endothelium of neonatal IUGR arteries also displayed marked expression of angotensin (ANG). Indeed, ANGII inhibition in neonatal arteries completely reversed the pathological endothelial effects of IUGR, including restoration of normal endothelial dilator activity and organization of endothelial AJs. We therefore propose that IUGR disrupts the early postnatal maturation of arterial endothelium resulting in retention of an unusual newborn endothelial phenotype. This disruption appears to be mediated by IUGR-induced local generation of ANGII and activation of endothelial AT1 receptors. We further propose that within the IUGR arterial wall, the local production of ANGII and other components of the immature endothelium will be powerful stimuli for vascular remodeling and cardiovascular diseases associated with IUGR. Three independent and interactive aims will investigate 1) Effects of IUGR on the Postnatal Maturation of Arterial Endothelium, 2) The Role of a Local Angiotensin System in Mediating Endothelial Effects of IUGR, and 3) Disrupted Endothelial Maturation and the Cardiovascular Pathology of IUGR

Public Health Relevance

Considerable epidemiological and experimental data indicates that poor in utero conditions can increase an individual's risk for developing cardiovascular and metabolic diseases, including hypertension and diabetes. By using mice models to investigate this 'developmental origins of adult disease', we have identified important early defects in the maturation of IUGR vascular cells. Our research promises to uncover novel mechanisms responsible for the subsequent development of cardiovascular disease and to identify new treatment options.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Pregnancy and Neonatology Study Section (PN)
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Raiten, Daniel J
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Johns Hopkins University
Schools of Medicine
United States
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Chang, Fumin; Flavahan, Sheila; Flavahan, Nicholas A (2016) Immature endothelial cells initiate endothelin-mediated constriction of newborn arteries. J Physiol 594:4933-44
Zhao, Yingzi; Flavahan, Sheila; Leung, Susan W et al. (2015) Elevated pressure causes endothelial dysfunction in mouse carotid arteries by increasing local angiotensin signaling. Am J Physiol Heart Circ Physiol 308:H358-63
Flavahan, Sheila; Flavahan, Nicholas A (2014) The atypical structure and function of newborn arterial endothelium is mediated by Rho/Rho kinase signaling. Am J Physiol Heart Circ Physiol 307:H628-32