Recent evidence suggests that pulmonary vascular tone is regulated by a complex interaction of vasoactive substances that are locally produced by the vascular endothelium, such as nitric oxide (NO) and endothelin-1 (ET-1). Endothelial injury secondary to increased pulmonary blood flow and/or pressure disrupts these regulatory mechanisms, and is a potential factor in the development of a number of cardiovascular diseases including pulmonary hypertension. However, the mechanisms by which the endothelial dysfunction occurs have not been adequately resolved. We have established a lamb model of pulmonary hypertension secondary to increased pulmonary blood flow. In this model, similar to infants born with ventricular septal defects, there is an increase in the expression of the genes that induce pulmonary vasoconstriction and a reduction in those that induce vasodilation. In the initial funding period we have demonstrated that increased reactive oxygen species (ROS) generation in the pulmonary vessels is associated with the development of pulmonary hypertension and that ROS scavengers normalize the vasodilator response in pulmonary vessels isolated from these lambs. We have also demonstrated that these increases in ROS are associated with decreased NO-signaling. In addition, our new preliminary data indicate that the increased ROS generation correlates with the elevation in the levels of the endogenous NOS inhibitor, asymmetric dimethyl arginine (ADMA) and decreases in the levels of the NOS co-factor tetrahydrobiopterin (BH4). Further, we have obtained evidence that mitochondrial dysfunction, secondary to disruptions of carnitine metabolism, appears to play an important role in the endothelial dysfunction associated with the development of pulmonary hypertension. Thus, in this competitive renewal we plan to elucidate the mechanisms by which mitochondrial dysfunction occurs and elucidate the role played by ADMA in this process. We anticipate that the successful completion of our studies will significantly increase our understanding of the mechanisms underlying the diminished NO-signaling and endothelial dysfunction associated with the development of pulmonary hypertension secondary to increased pulmonary blood flow. Further, our studies may suggest new signaling pathways that may have clinical utility for the treatment of infants and children with pulmonary hypertension.
The incidence of congenital heart defects in the U.S. is ~1 per 100 live births. Approximately 50% of these children require medical and/or surgical attention. The majority of defects requiring treatment are associated with increased pulmonary blood flow. This includes children born with ventricular septal defect, truncus arteriosus, or atrioventricular septal defect. Survival for children born with congenital heart defects has improved because of the development of new diagnostic tools, and advances in surgical techniques and post-operative management. However, these children continue to suffer significant morbidity and late mortality, in part because of abnormal vascular reactivity leading to endothelial dysfunction within the pulmonary circulation. The factors responsible for the development of endothelial dysfunction are incompletely understood. A better understanding of the cellular and molecular mechanisms that underlie the development of endothelial dysfunction will lead to improved survival for newborns, infants, and children with congenital heart defects. Thus, the studies in this proposal to investigate the mechanism for the progressive decrease in NO-Signaling seen in our lamb model of congenital heart disease and increased pulmonary blood flow have the potential to significantly impact the survival of children born with congenital heart defects.
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