Therapies for preventing the onset or progression of neonatal pulmonary hypertension have received little attention and have largely targeted the nitric oxide pathway. Our findings indicate that an interplay between the prostanoid and NADPH oxidase signaling pathways plays a key role early in the development of chronic hypoxia-induced neonatal pulmonary hypertension. Our overall hypothesis is that within 3 days exposure to hypoxia, disruptions in prostanoid and NADPH oxidase signaling occur which mediate changes in smooth muscle cell (SMC) reactive oxygen species (ROS) production and voltage-gated K+ (Kv) channel function. These changes create a feed-forward process that self-perpetuates vascular dysfunction and is amplified when hypoxia is extended to 10 days. The specific hypotheses are: chronic hypoxia (1) activates prostanoid and NADPH oxidase pathways leading to elevated constrictor prostanoid production and ROS generation in SMCs of pulmonary resistance arteries (PRAs) which in turn (2) impairs SMC Kv channel function, causing SMC membrane (Em) depolarization and elevated cytosolic calcium concentration.
Specific Aim 1 will determine the effect of 3 or 10 days hypoxia on (a) relative contributions of prostanoid and NADPH oxidase signaling pathways to ROS production and aberrant PRA responses (using cannulated PRA, lucigenin- derived chemiluminescence, oxidant-sensitive fluorescent dye, and cultured SMC techniques) and (b) amounts (immunoblot), activity (enzyme assays) and predominant cellular locations (immunohistochemistry) of NADPH oxidase and superoxide dismutases. Key findings will be validated with in vivo studies.
Specific Aim 2 will evaluate the effect of 3 or 10 days hypoxia on (a) contribution of Kv channels to vascular tone (cannulated arteries) (b) SMC Em (microelectrode) (c) SMC Ca2+ (fluorescence) and (d) Kv channel amounts (immunoblot). Our findings will provide new information needed to devise therapies to intervene with the development of pulmonary hypertension in infants with conditions associated with chronic hypoxia. Relevance: Pulmonary hypertension is a well recognized complication of infants with a variety of lung and heart disorders. Currently there are few good options for treating these infants. The goal of this project is to help us understand why infants develop pulmonary hypertension, determine what happens in the lung blood vessels during disease development, and develop treatments for this disease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068572-06
Application #
7256220
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Blaisdell, Carol J
Project Start
2001-12-01
Project End
2010-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
6
Fiscal Year
2007
Total Cost
$335,359
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Fike, Candice D; Aschner, Judy L; Kaplowitz, Mark R et al. (2013) Reactive oxygen species scavengers improve voltage-gated K(+) channel function in pulmonary arteries of newborn pigs with progressive hypoxia-induced pulmonary hypertension. Pulm Circ 3:551-63
Fike, Candice D; Dikalova, Anna; Slaughter, James C et al. (2013) Reactive oxygen species-reducing strategies improve pulmonary arterial responses to nitric oxide in piglets with chronic hypoxia-induced pulmonary hypertension. Antioxid Redox Signal 18:1727-38
Fike, Candice D; Aschner, Judy L (2013) Looking beyond PPHN: the unmet challenge of chronic progressive pulmonary hypertension in the newborn. Pulm Circ 3:454-66
Fike, Candice D; Aschner, Judy L (2013) Spread the word, children are still not ""small adults"". Pulm Circ 3:3-4
Fike, Candice D; Kaplowitz, Mark; Zhang, Yongmei et al. (2012) Effect of a phosphodiesterase 5 inhibitor on pulmonary and cerebral arteries of newborn piglets with chronic hypoxia-induced pulmonary hypertension. Neonatology 101:28-39
Fike, Candice D; Sidoryk-Wegrzynowicz, Marta; Aschner, Michael et al. (2012) Prolonged hypoxia augments L-citrulline transport by system A in the newborn piglet pulmonary circulation. Cardiovasc Res 95:375-84
Fike, Candice D; Aschner, Judy L; Slaughter, James C et al. (2011) Pulmonary arterial responses to reactive oxygen species are altered in newborn piglets with chronic hypoxia-induced pulmonary hypertension. Pediatr Res 70:136-41
Fike, Candice D; Pfister, Sandra L; Slaughter, James C et al. (2010) Protein complex formation with heat shock protein 90 in chronic hypoxia-induced pulmonary hypertension in newborn piglets. Am J Physiol Heart Circ Physiol 299:H1190-204
Aschner, Judy L; Zeng, Heng; Kaplowitz, Mark R et al. (2009) Heat shock protein 90-eNOS interactions mature with postnatal age in the pulmonary circulation of the piglet. Am J Physiol Lung Cell Mol Physiol 296:L555-64
Dennis, Kathleen E; Aschner, J L; Milatovic, D et al. (2009) NADPH oxidases and reactive oxygen species at different stages of chronic hypoxia-induced pulmonary hypertension in newborn piglets. Am J Physiol Lung Cell Mol Physiol 297:L596-607

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