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Page 4 of 10 Balistreri. Vessel Plus 2018;2:25 I http://dx.doi.org/10.20517/2574-1209.2018.35

Table 1. Mechanisms and pathways identified using apposite PHN models
Mechanisms and pathways Models
Functional reductions in soluble guanylyl cyclase (sGC) function and cyclic guanosine Utero ligation of the ductus
monophosphate (cGMP)-dependent vasorelaxation arteriosus and chronic perinatal
Increased phosphodiesterase type 5 (PDE5) and enhanced Endothelin-1 (ET-1) contraction; hypoxia in sheep fetuses and
Significant decrease of levels of endothelial nitric oxide synthase (eNOS) newborns
Significant reduction in calcium activated potassium channels (BKCa)
Increase of these last molecules in chronic hypoxia
Important pulmonary arterial pressure (P PA ) Antenatal and/or postnatal hypoxic
Altered relaxation and augmented contractility of pulmonary arteries (PAs) exposure in mice
Hyperplasia of pulmonary arterial smooth muscle cells (PASMCs) and improved actin
polymerization, and adventitial fibroblast proliferation.
Rare group of the microvasculature and augmented smooth muscle actin expression in Short-term hyperoxia in mice:
distal PAs, changes that are associated with down-regulation of the bone morphogenetic a model of bronchopulmonary
proteins (BMP) signaling pathway in affected lungs dysplasia (BPD)
Persistent alterations in lung structure.
Vascular defects, predisposing the lung to PH later in life, while in neonates it induces an Neonatal hyperoxia
adaptive mechanism, which occurs in the right ventricular (RV) increasing the tolerance
Oxidative stress: high levels of reactive oxygen species (ROS) related to hyperoxia, High altitude and assisted
mechanical ventilation, hypoxia, and inflammation reproductive technologies (ART)
Epigenetic alterations
Systemic vascular dysfunction in the progeny from both animals and humans. This seems Maternal undernutrition
to be associated with an increase of ROS in placenta, which induce epigenetic alterations,
such as lung DNA methylation epigenetic mechanisms, such as an altered DNA
methylation and gene expressions of conserved pathways, such as Notch pathway
End-products of endothelial-derived nitric oxide (NO) heme-oxidation, nitrate and nitrite Alteration in maternal microbiome
produce exogenous NO, which mediates an increased vasoactive signaling activity during
hypoxia and stress

altered development of pulmonary microvasculature, including PHN, which affects newborns. Offspring
with PHN have aberrantly reactive or overly muscular vessels and show acute and chronic states of PHN,
characterized by difficulty to adapt to breathing during the birth transition and early postnatal period. PHN
[3]
is associated with a high morbidity and mortality . The etiology’s factors of PHN are diverse, ranging from
high-altitude living, maternal malnutrition, placental insufficiency due to environmental factors or diseases,
such as preeclampsia, to other pregnancy complications, such as infections (i.e., staphylococcus infection) or
[3]
drugs . The number of newborns affected by PHN might increase, given the rise in adverse environmental
factors or other causes in our Western society. Consequently, the investigations for identifying mechanisms
and pathways are imperative. Of note are the experimental investigations on animal models, given the
inadequate availability of patient tissues and inability to perform mechanistic studies in humans. Several
animal PH’s models have been developed for performing studies into the functional and structural changes,
which occur during the development of pulmonary circulation and PH [21-34] . Unfortunately, to date not
a single preclinical model perfectly replicates human PH. Nonetheless, the models used provide the
opportunity to characterize the development and progression of PH, to perform mechanistic studies, and to
evaluate potential therapeutic treatments. In addition, the developed models could also permit to identify
the mechanisms and pathways involved, which appear to be dependent on the type and grade of stress to
which the fetus is subjected. They are illustrated in Table 1.

The multitude of models reported in literature is described in detail in the next paragraph, as well as the
mechanisms and pathways identified and reported in Table 1.

The relevant models for PHN
Some relevant models for PHN have been developed and studied. Of note are the results obtained by the
[22]
utero ligation of the ductus arteriosus and chronic perinatal hypoxia in sheep fetuses and newborns .
They have demonstrated that the mechanisms associated with PH are dependent on the type and grade of
[22]
stress to which the fetus is subjected . Specifically, similarities were observed between the ligation and