de Wijs-Meijler Daphne P M, Duncker Dirk J, Danser A H Jan, Reiss Irwin K M, Merkus Daphne
Division of Experimental Cardiology, Department of Cardiology, University Medical Center Rotterdam, Erasmus MC, Rotterdam, The Netherlands.
Division of Neonatology, Department of Pediatrics, Sophia Children's Hospital, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Physiol Rep. 2018 Oct;6(20):e13889. doi: 10.14814/phy2.13889.
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.
新生儿肺血管疾病（PVD）越来越被认为是一种使出生后心肺适应过程复杂化并易引发长期心肺疾病的疾病。越来越多的证据表明，PVD与一氧化氮（NO）-环磷酸鸟苷（cGMP）-磷酸二酯酶5（PDE5）通路的破坏有关。为了更好地理解新生儿PVD的发病机制，需要对该通路不同部分的功能进行研究。为此，在一个缺氧诱导PVD的新生猪模型中，研究了NO-cGMP-PDE5通路在体内静息和运动状态下以及体外分离的肺小动脉中对肺血管功能调节的作用。缺氧诱导PVD的仔猪在体内静息和体外时，内皮依赖性血管舒张功能均受损。此外，缺氧仔猪在体内对NO供体硝普钠（SNP）的反应性降低，而在体外对SNP和8-溴环鸟苷酸的舒张反应未改变。最后，缺氧仔猪在体外和体内静息时，PDE5抑制诱导的肺血管舒张功能均受损。然而，在运动过程中，与常氧暴露仔猪相比，缺氧暴露仔猪中PDE5抑制的肺血管舒张作用明显更大。总之，缺氧诱导PVD的仔猪内皮依赖性血管舒张功能受损，同时对NO的反应性降低，这可能是由于可溶性鸟苷酸环化酶（sGC）的敏感性和/或活性改变导致cGMP生成受损所致。我们在新生儿PVD新生动物模型中的研究结果表明，sGC刺激剂/激活剂可能是缓解新生儿PVD的一种新的治疗策略。
