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

of systemic arteries, because of a reduced vascular smooth muscle component and a relative absence
[1]
of adventitial components . However, the lung circulation system has some factors able to control the
pulmonary blood flow, like the systemic vascular system. They firstly include vascular structure, gravity, and
[1]
mechanical effects of breathing . Furthermore, neural and humoral factors are also involved.
[1]
Another feature of PAs is the susceptibility of pulmonary vascular tone for hypoxia . Temporary hypoxia
provokes pulmonary vasoconstriction, but, if persistent, it contributes to the onset of vascular remodeling
[2]
and dysfunction, which results in the development of pulmonary hypertension (PH) . PH is defined by
abnormally high pulmonary artery pressure, which can occur in numerous diseases and clinical situations.
The hypoxemia represents one of the five major causes of PH. Accordingly, the 2015 ECS/ERS guidelines in
the treatment and diagnosis of PH have assembled the different forms of PH related to diverse causes in five
[3]
major groups . Consistent with the recent guidelines, genetic and environmental factors represent other
crucial factors of PH susceptibility. For example, pathogen infections [i.e., human immunodeficiency virus
(HIV) infection] and the related inflammatory responses constitute the common causes of their onset, by
[4,5]
altering the normal pulmonary endothelium barrier and causing edema . Other inflammatory conditions
not related to pathogens are also involved. For examples, autoimmune disorders, with a female predomi-
[5]
nance, are significantly associated with the onset of PH . Regarding genetic factors, several research groups,
from diverse European and US countries, have recently summarized all the established and emerging molec-
ular defects related or not to familial pulmonary arterial hypertension (PAH) forms, which include not only
mutations in the bone morphogenetic protein receptor type II (BMPR2) gene, defects of the transforming
growth factor beta pathway, but also defects in activin A receptor type II-like 1 (ACVRL1), endoglin (ENG),
[6]
and members of the SMAD family .
[7]
Recently, Gao et al. have emphasized that an impairment of the normal development of pulmonary
vasculature is involved in the pathogenesis of different paediatric pulmonary pathologies, PH included.
In addition, they have particularly suggested that the principal target of this process is the endothelium.
Accordingly, they have speculated that the identification of mechanisms and pathways, preserving both
endothelial maturation and function, might improve the development of the entire lung. Furthermore, they
also hypothesized that these mechanisms and pathways have long-term favourable effects in diverse forms
of neonatal PH related not only to preterm birth and onset of lung diseases, but also to congenital heart
[7]
diseases .

Consistent with these last findings, it appears reasonable that PH may also be the result of the developmental
programming (DP) of adult diseases, as emphasized by fetal origin of adult diseases theory postulated by
[8]
Barker . PH in neonates (PHN) has been demonstrated to be the result of several adverse events during
intra-utero/perinatal life, including high-altitude living, maternal malnutrition, placental insufficiency related
to environmental factors or diseases such as preeclampsia, infections (i.e., staphylococcus infection), drugs,
[3]
alcohol, etc. . Currently, the knowledge of the related mechanisms and pathways involved is imperative,
because of the increased morbidity and mortality related to this PH group and the rise of prevalence in
the new-borns, linked to the increase in unfavourable environmental factors in our populations. Their
identification might facilitate the development of effective therapies or measures. Here, established literature
evidence will be described and discussed.

THE RELATIONSHIP BETWEEN DP AND PH: FOCUS ON EPIGENETIC FACTORS
There is, in literature, a well-established evidence of DP in eutherian mammals, humans included. DP is the
result of evolution’s machinery, which determines, on the late, the utero and placentation development for
[9]
guaranteeing an optimal intrauterine life .
Accordingly, protection and nutritional support are the utero and placenta’s functions. On the other late,