With the initiation of ventilation and oxygenation at birth, pulmonary vascular resistance decreases and pulmonary blood flow increases. There is evidence that increased endothelial NO synthase (eNOS) gene expression, eNOS activity, and NO production contribute to these changes. However, in a number of clinical conditions, there is failure of the pulmonary circulation to undergo this normal transition to postnatal life, resulting in persistent pulmonary hypertension of the newborn (PPHN). PPHN complicates more than 1 in 1000 live birth and up to 10% of admissions to intensive care units. PPHN causes substantial morbidity and mortality in otherwise normal term infants. Newborns who die of PPHN have decreased endogenous NO production and an increase in circulating endothelin (ET-1) levels. In addition these children have an increase in pulmonary arterial medial smooth muscle cell thickness and extension of muscle to normally non muscular arteries. The anatomic changes in the pulmonary vessels in newborns with PPHN are thought to be intimately associated with the morbidity and mortality associated with PPHN. However, the mechanisms producing this abnormal smooth muscle cell (SMC) development and the reduction in ENOS gene expression and NO production are not well understood. We hypothesize that the increased circulating levels of ET-1 in infants with PPHN activates the ETS subtype receptor located in the SMC layer leading to an increase in the production of reactive oxygen species (ROS) in these cells. This increase in ROS then stimulates SMC proliferation while decreasing endogenous ENOS expression in endothelial cells by inhibiting the transcription of its gene. To test these hypotheses we will investigate the following: 1) How does ET-1 stimulate ROS generation in SMCs? 2) Are the increased levels of ROS induced by ET-1 linked to an increase in SMC proliferation? 3) Does ROS reduce, while antioxidants increase, eNOS gene expression in endothelial cells? The successful completion of these studies will lead to a better understanding of the mechanisms responsible for the development of PPHN and may lead to new treatments for infants born with pulmonary hypertension.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Human Embryology and Development Subcommittee 1 (HED)
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Berberich, Mary Anne
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University of Montana
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Schools of Pharmacy
United States
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