Page 21 - Read Online

Balistreri. Vessel Plus 2018;2:25 I http://dx.doi.org/10.20517/2574-1209.2018.35 Page 3 of 10

this implies that foetal development happens by adapting to the micro-environment and maternal (or
better paternal) endogenous and exogenous stressors. Consequently, both development and fate of tissues,
organs, and systems of an offspring can result in an altered or greater susceptibility to onset of ageing and
[9]
pathologies . The process of genomic imprinting is the principal driver of these alterations, and it consists
[9]
of an uncommon epigenetic process . It provides effects on new-borns, principally through maternal DNA
methylation imprints. Today, other epigenetic mechanisms (i.e., histone modifications, antisense noncoding
RNA (ncRNA)-mediated silencing, long-range chromatin interactions, and expression of microRNA), have
[9]
been suggested to mediate genomic imprinting . However, their actions remain unclear, even if it firstly
supposes their capacity of modulating the expression of a wide range of imprinted genes restricted to specific
[9]
foetal tissues, particularly the placenta, hypothalamus, and endothelium . Contemporarily, the developing
placenta and hypothalamus influence the expression of the foetal genome, which results in the release of
hormones able to impact the functions of both foetal and maternal hypothalamus. This control consents
the foetal hypothalamus to regulate the development of organs and systems of the foetus, such as the
[9]
pulmonary circulation . Maternal insults or stressors, including maternal nutritional changes, hormones
(i.e., cortisol), other lifestyle stressors (e.g., obesity, smoking, drugs, alcohol), and the clinical status can
alter maternal imprinting. This results in the onset of pathological conditions during pregnancy, including
[9]
intrauterine growth restriction (IUGR) and preeclampsia . On the other hand, IUGR and preeclampsia have
been demonstrated to be significantly associated with the development of several pathologies in neonates,
[9]
such as PHN . IUGR neonates show prematurity and related immediate medical problems, and a notable
susceptibility for hypertension, PH, cardiovascular diseases, diabetes, and neurodegenerative diseases in
adult age, likely through the effects of foetal programming.

The principal target of foetal programming: the endothelium
Endothelial dysfunction is the pathological condition associated with the onset of many pathologies related
not only to the cardiovascular system, but also to the cardio-pulmonary circuit, as well as to developmental
of disease in other tissues, principally correlated to the ageing process. This close relationship derives from
the function of endothelium itself, which is the essential element of stroma of all tissues. Our and other
groups emphasise this concept as being of great importance in understanding the complex pathophysiology
of diseases, such as those of the cardiovascular and pulmonary systems [10-13] .

Endothelium has been demonstrated to be the major target of fetal programming. Its alterations and
dysfunction primordially seem to originate from adverse parental and foetal environment conditions.
Accordingly, recent experimental data have demonstrated that the levels of vascular endothelial growth
factor (VEGF), its receptors and transcription factors, useful for the correct maturation and differentiation
of foetal endothelium, are modulated by several adverse conditions, such as chronic hypoxia, maternal food
[14]
restriction, altered levels of glucocorticoids, and microRNA . Other findings report that chronic hypoxia
and altered maternal clinical conditions can impact the maturation and differentiation of endothelium
and the vasculature of all the tissue districts, ranging from foeto-placental arteries, carotid arteries,
myocardium, to cerebrovascular systems, renal, liver, and PAs [15-17] . Another study also demonstrates that
the IUGR condition in rats affects the function of both endothelium cells and their progenitors. Specifically,
IUGR appears to induce vasodilatation, by modulating the expression and function of some molecules and
[18]
pathways, such as acetylcholine and nitric oxide (NO) pathways, respectively . Metabolic alterations related
to IUGR condition have been also demonstrated to contribute to an altered development of endothelium and
[20]
[19]
its dysfunction . Musa et al. , have recently reviewed the results from about 230 studies, on the key role of
maternal and intrauterine conditions on endothelium structural and function of offspring, by reporting all
the related alterations mechanisms and pathways involved.

PHN AND FOETAL PROGRAMMING: FOCUS ON MECHANISMS AND PATHWAYS INVOLVED
[3]
One of five PH groups, established by 2015 ECS/ERS 2015 guidelines , consists of PH diseases related to an