CGMP REGULATION IN THE DEVELOPING PULMONARY VASCULATURE

Project: Research project

Description

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.
StatusFinished
Effective start/end date8/1/956/30/15

Funding

  • National Institutes of Health: $474,677.00
  • National Institutes of Health: $433,942.00
  • National Institutes of Health
  • National Institutes of Health: $319,790.00
  • National Institutes of Health: $471,401.00
  • National Institutes of Health: $431,248.00
  • National Institutes of Health
  • National Institutes of Health: $454,932.00
  • National Institutes of Health: $282,740.00
  • National Institutes of Health: $97,148.00
  • National Institutes of Health: $280,886.00
  • National Institutes of Health: $504,934.00
  • National Institutes of Health: $457,761.00
  • National Institutes of Health: $447,755.00
  • National Institutes of Health: $278,976.00
  • National Institutes of Health

Fingerprint

Persistent Fetal Circulation Syndrome
Lung
Nitric Oxide
Parturition
Blood Vessels
Phosphoric Diester Hydrolases
Pulmonary Hypertension
Oxidation-Reduction
Reactive Oxygen Species
Vascular Smooth Muscle
Gases
Ductus Arteriosus
Enzymes
Oxygen
Vascular Resistance
Hyperoxia
Guanylate Cyclase
Poisons
Cyclic GMP
Vascular Endothelium

ASJC

  • Medicine(all)