The normal transition of gas exchange from the placenta to the lungs at birth depends on a 10-fold increase in pulmonary blood flow, and a sharp decline in pulmonary arterial pressure. This in turn depends upon a dramatic decrease in pulmonary vascular tone. An important stimulus for these events is the increase in alveolar oxygen tension that occurs at birth. Nitric oxide production by the vascular endothelium has been shown to play an integral role in the regulation of vascular tone. Nitric oxide activates the soluble guanylate cyclase enzyme system in vascular smooth muscle to produce cGMP, which mediates relaxation. Cyclic GMP is hydrolyzed and inactivated by phosphodiesterases. Nitric oxide production by the endothelium has been established as having an important role in the transition at birth, and may be developmentally regulated. However, the developmental time sequences for the equally important soluble guanylate cyclase and phosphodiesterase enzyme systems are poorly understood. Understanding the mechanisms producing the transition at birth is important, because in some newborn infants, the normal decrease in pulmonary vascular resistance and increase in pulmonary blood flow does not occur, resulting in persistent pulmonary hypertension of the newborn (PPHN). This syndrome results in substantial morbidity and mortality in otherwise normal term infants. Even though a role for endothelial nitric oxide production has been established in the normal transition at birth, no direct evidence points to decreased nitric oxide synthesis as the cause of persistent pulmonary hypertension. Despite this, inhalation of nitric oxide, a toxic and carcinogenic gas, is being investigated as a treatment for PPHN. We have studied an animal model of persistent pulmonary hypertension produced by ligating the ductus arteriosus of the fetal lamb before birth. We have data that accumulation of cGMP by soluble guanylate cyclase in response to nitric oxide is abnormal in this mode. A decrease in cGMP accumulation in response to endogenous NO may explain why some newborns have persistent pulmonary hypertension. It may further explain why some infants with PPHN do not respond initially, or do not maintain their response to inhaled NO. We therefore propose to study the normal developmental time sequence for the guanylate cyclase enzyme systems producing cGMP, and the phosphodiesterase systems inactivating cGMP in vascular smooth muscle. We will study the effect of oxygen as a direct stimulus for increasing cGMP production, and study whether it potentiates other stimuli which increase cGMP concentrations. Finally, we will study regulation of cGMP production and inactivation in the lamb model of persistent pulmonary hypertension. These data should have direct relevance to a better understanding of the causes of PPHN, and allow the design of safer, more effective treatments.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29HL054705-03
Application #
2460136
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1995-08-01
Project End
1999-07-31
Budget Start
1997-08-01
Budget End
1998-07-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
State University of New York at Buffalo
Department
Pediatrics
Type
Schools of Medicine
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Wedgwood, Stephen; Lakshminrusimha, Satyan; Schumacker, Paul T et al. (2015) Cyclic stretch stimulates mitochondrial reactive oxygen species and Nox4 signaling in pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 309:L196-203
Heilman, Rachel P; Lagoski, Megan B; Lee, Keng Jin et al. (2015) Right ventricular cyclic nucleotide signaling is decreased in hyperoxia-induced pulmonary hypertension in neonatal mice. Am J Physiol Heart Circ Physiol 308:H1575-82
Lee, Keng Jin; Berkelhamer, Sara K; Kim, Gina A et al. (2014) Disrupted pulmonary artery cyclic guanosine monophosphate signaling in mice with hyperoxia-induced pulmonary hypertension. Am J Respir Cell Mol Biol 50:369-78
Ball, Molly K; Waypa, Gregory B; Mungai, Paul T et al. (2014) Regulation of hypoxia-induced pulmonary hypertension by vascular smooth muscle hypoxia-inducible factor-1?. Am J Respir Crit Care Med 189:314-24
Berkelhamer, Sara K; Mestan, Karen K; Steinhorn, Robin H (2013) Pulmonary hypertension in bronchopulmonary dysplasia. Semin Perinatol 37:124-31
Lakshminrusimha, Satyan; Steinhorn, Robin H (2013) Inodilators in nitric oxide resistant persistent pulmonary hypertension of the newborn. Pediatr Crit Care Med 14:107-9
Perez, Marta; Lakshminrusimha, Satyan; Wedgwood, Stephen et al. (2012) Hydrocortisone normalizes oxygenation and cGMP regulation in lambs with persistent pulmonary hypertension of the newborn. Am J Physiol Lung Cell Mol Physiol 302:L595-603
Farrow, Kathryn N; Lee, Keng Jin; Perez, Marta et al. (2012) Brief hyperoxia increases mitochondrial oxidation and increases phosphodiesterase 5 activity in fetal pulmonary artery smooth muscle cells. Antioxid Redox Signal 17:460-70
Wedgwood, Stephen; Lakshminrusimha, Satyan; Farrow, Kathryn N et al. (2012) Apocynin improves oxygenation and increases eNOS in persistent pulmonary hypertension of the newborn. Am J Physiol Lung Cell Mol Physiol 302:L616-26
Bishop, Naomi B; Stankiewicz, Pawel; Steinhorn, Robin H (2011) Alveolar capillary dysplasia. Am J Respir Crit Care Med 184:172-9

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