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Balistreri. Vessel Plus 2018;2:25 I http://dx.doi.org/10.20517/2574-1209.2018.35 Page 5 of 10
hypoxia models, in functional reductions in soluble guanylyl cyclase (sGC) function, cyclic guanosine
monophosphate (cGMP)-dependent vasorelaxation, increased phosphodiesterase type 5 (PDE5) and enhanced
Endothelin-1 (ET-1) contraction. In contrast, significant differences were found in the cellular processes
between the two models: a significant decrease in the levels of endothelial nitric oxide synthase (eNOS) and
calcium activated potassium channels (BKCa) in ligation models; an increase of these molecules in chronic
[22]
hypoxia . Other models for PHN are the exposure-based models, including short-term neonatal hyperoxia,
fetal and/or post-natal hypoxia and a two-hit model of prenatal hypoxia followed by postnatal hyperoxia.
Among these, the antenatal and/or postnatal hypoxic exposure in mice are significantly associated with the
onset of an important pulmonary arterial pressure (P ), altered relaxation and augmented contractility of
PA
PAs, hyperplasia of pulmonary arterial smooth muscle cells (PASMCs) and improved actin polymerization,
and adventitial fibroblast proliferation [23-25] . Short-term hyperoxia in mice, which is used as typical model of
bronchopulmonary dysplasia (BPD), impacts the microvasculature and shows an augmented smooth muscle
actin expression in distal PAs. These changes are also associated with the down-regulation of the bone
[26]
morphogenetic proteins (BMP) signaling pathway in affected lungs . Relevant are the recent findings on
short-term neonatal exposure to hyperoxia. This condition is characterized to induce not directly PH, but it
[27]
may predispose adults to PH , because of persistent alterations in lung structure. On the contrary, neonatal
hyperoxia has been demonstrated to be advantageous for right ventricular (RV) hypertrophy. This has led
to the hypothesis that this exposure shows two different effects: it can cause vascular defects, predisposing
the lung to PH later in life, while in neonates it induces an adaptive mechanism, which occurs in the RV,
[28]
[27]
increasing the tolerance . Other models are the high altitude and assisted reproductive technologies
(ART) , that have represented the models typically used by the Sartori group. They have consented to
[29]
evidence the role of oxidative stress and/or epigenetic alterations during foetal programming and the
altered onset of pulmonary circulation [30,31] . Consistent with these efforts and advances, reactive oxygen
species (ROS) seem to have an important role in the pathogenesis of neonatal pulmonary vascular diseases,
such as PHN. High levels of ROS may be produced in conditions of hyperoxia, mechanical ventilation,
hypoxia, and inflammation. These data may be of crucial relevance in individuals born premature, who
show a high risk of the long-term complications of pulmonary vascular diseases, thereby contributing to
[32]
[31]
the increase of incidence of adult cardiovascular disease . Maternal undernutrition during pregnancy
has been used as another model for identifying the fundamental mechanisms, which occur in the altered
[31]
development of pulmonary circulation and the onset of PHN . This condition provokes systemic vascular
dysfunction in the progeny from both animals and humans. Precisely, in rats, restrictive diet during
pregnancy (RDP) raises oxidative stress in the placenta. ROS induce epigenetic alterations and can cross the
placental barrier. An altered lung DNA methylation has been detected and is correlated with pulmonary
vascular dysfunction. This datum has been confirmed using the treatment with histone deacetylase
[31]
inhibitors butyrate and trichostatin A in RDP newborns . These results suggest that the condition of
undernutrition during gestation can contribute to an altered development of the cardiopulmonary system
and the consequent onset of vascular dysfunction in the new generation through the actions of epigenetic
mechanisms, such as an altered DNA methylation and gene expressions of conserved pathways, such as
[31]
Notch pathway . Accordingly, another investigation has evidenced the key importance of Notch pathway
[33]
in the developmental alterations of cardiopulmonary circuit and the onset of PHN . Recent evidence also
underlines a key role of maternal microbiome in the onset of cardiac and pulmonary vascular diseases, such
[34]
as PHN . Specifically, it has been reported that end-products of endothelial-derived NO heme-oxidation,
nitrate and nitrite produce exogenous NO, which mediates an increased vasoactive signaling activity during
hypoxia and stress. The levels of nitrate and nitrite depend on the enzymatic reduction of nitrate to nitrite
by bacterial nitrate reductase enzymes, expressed by precise bacterial gut populations . Such as result,
[34]
PH seems to be related to alterations in NO signaling, by suggesting a role of commensal oral bacteria in
[34]
contributing to the onset of PH through the formation of nitrite, NO and other bioactive nitrogen oxides .
This evidence is supported by oral supplementation with inorganic nitrate or nitrate-containing foods, which
are shown to have pleiotropic, useful vascular effects in the setting of inflammation, endothelial dysfunction,