Changes in the nitric oxide pathway of the pulmonary vasculature after exposure to hypoxia in swine model of neonatal pulmonary vascular disease

Abstract

Neonatal pulmonary vascular disease (PVD) is increasingly recognized as a disease that complicates the cardiopulmonary adaptations after birth and predisposes to long‐term cardiopulmonary disease. There is growing evidence that PVD is associated with disruptions in the nitric oxide (NO)‐cGMP‐phosphodiesterase 5 (PDE5) pathway. Examination of the functionality of different parts of this pathway is required for better understanding of the pathogenesis of neonatal PVD. For this purpose, the role of the NO‐cGMP‐PDE5 pathway in regulation of pulmonary vascular function was investigated in vivo, both at rest and during exercise, and in isolated pulmonary small arteries in vitro, in a neonatal swine model with hypoxia‐induced PVD. Endothelium‐dependent vasodilatation was impaired in piglets with hypoxia‐induced PVD both in vivo at rest and in vitro. Moreover, the responsiveness to the NO‐donor SNP was reduced in hypoxia‐exposed piglets in vivo, while the relaxation to SNP and 8‐bromo‐cyclicGMP in vitro were unaltered. Finally, PDE5 inhibition‐induced pulmonary vasodilatation was impaired in hypoxia‐exposed piglets both in vitro and in vivo at rest. During exercise, however, the pulmonary vasodilator effect of PDE5 inhibition was significantly larger in hypoxia‐exposed as compared to normoxia‐exposed piglets. In conclusion, the impaired endothelium‐dependent vasodilatation in piglets with hypoxia‐induced PVD was accompanied by reduced responsiveness to NO, potentially caused by altered sensitivity and/or activity of soluble guanylyl cyclase (sGC), resulting in an impaired cGMP production. Our findings in a newborn animal model for neonatal PVD suggests that sGC stimulators/activators may be a novel treatment strategy to alleviate neonatal PVD.

Therapies that enhance pulmonary vascular NO-signaling in the neonate

“…Moreover, PDE5 induction in the PPHN lamb model has been linked to mitochondrial oxidative stress with rapid increases in mitochondrial ROS and PDE5 activity within 30 minutes of hyperoxia exposure (103). Similarly, PDE5 activation and impairments in cGMP production have been reported in other neonatal models associated with increased oxidative stress, including a swine model of hypoxia-induced pulmonary vascular disease and a neonatal mouse model of HLI (66,104), as well as in mice with chronic heart failure (70). Findings from animal models of PPHN also demonstrated that increased oxidative stress reduced the bioavailability of NO through eNOS uncoupling and downregulation of eNOS expression and function (101,105,106).…”