Intrauterine life represents a window of phenotypic plasticity which carries consequences for later health in adulthood as well as health of subsequent generations. Intrauterine growth-restricted fetuses (intrauterine growth restriction [IUGR]) have a higher risk of pulmonary arterial hypertension in adulthood. Endothelial dysfunction, characterized by hyperproliferation, invasive migration, and disordered angiogenesis, is a hallmark of pulmonary arterial hypertension pathogenesis. Growing evidence suggests that intergenerational transmission of disease, including metabolic syndrome, can be induced by IUGR. Epigenetic modification of the paternal germline is implicated in this transmission. However, it is unclear whether offspring of individuals born with IUGR are also at risk of developing pulmonary arterial hypertension and endothelial dysfunction. Using a model of maternal caloric restriction to induce IUGR, we found that first and second generations of IUGR exhibited elevated pulmonary arterial pressure, myocardial, and vascular remodeling after prolonged exposure to hypoxia. Primary pulmonary vascular endothelial cells (PVECs) from both first and second generations of IUGR exhibited greater proliferation, migration, and angiogenesis. Moreover, in 2 generations, PVECs-derived ET-1 (endothelin-1) was activated by IUGR and hypoxia, and its knockdown mitigated PVECs dysregulation. Most interestingly, within ET-1 first intron, reduced DNA methylation and enhanced tri-methylation of lysine 4 on histone H3 were observed in PVECs and sperm of first generation of IUGR, with DNA demethylation in PVECs of second generation of IUGR. These results suggest that IUGR permanently altered epigenetic signatures of ET-1 from the sperm and PVECs in the first generation, which was subsequently transferred to PVECs of offspring. This mechanism would yield 2 generations with endothelial dysfunction and pulmonary arterial hypertension–like pathophysiological features in adulthood.
Background
Increasing evidence revealed that airway microbial dysbiosis was associated with increased risk of asthma, or persistent wheezing (PW). However, the role of lung microbiota in PW or wheezing recurrence remains poorly understood.
Methods
In this prospective observational study, we performed a longitudinal 16S rRNA-based microbiome survey on bronchoalveolar lavage (BAL) samples collected from 35 infants with PW and 28 age-matched infants (control group). A 2-year follow-up study on these PW patients was conducted. The compositions of lower airway microbiota were analyzed at the phylum and genus levels.
Results
Our study showed a clear difference in lower airway microbiota between PW children and the control group. Children with PW had a higher abundance of Elizabethkingia and Rothia, and lower abundance of Fusobacterium compared with the control group. At the end of the 2-year follow-up, 20 children with PW (57.1%) experienced at least one episode of wheezing, and 15 (42.9%) did not suffer from wheezing episodes. Furthermore, PW children with recurrence also had increased abundances of Elizabethkingia and Rothia relative to those who had no recurrence. Additionally, wheezing history, different gender, and caesarean section demonstrated a greater impact in airway microbiota compositions.
Conclusion
This study suggests that the alterations of lower airway microbiota could be strongly associated with the development of wheezing, and early airway microbial changes could also be associated with wheezing recurrence later in life.
Background
Intrauterine growth retardation (
IUGR
) is related to pulmonary artery hypertension in adults, and mi
croRNA
‐206 (miR‐206) is proposed to affect the proliferation and apoptosis of pulmonary artery smooth muscle cells (
PASMC
s) via post‐transcriptional regulation.
Methods and Results
In an
IUGR
rat model, we found that the expression and function of potassium voltage‐gated channel subfamily A member 5 (Kv1.5) in
PASMC
s was inhibited, and pulmonary artery hypertension was exaggerated after chronic hypoxia (
CH
) treatment as adults. micro
RNA
expression was investigated in
PASMC
s from 12‐week‐old male
IUGR
rats with
CH
by microarray, polymerase chain reaction, and in situ hybridization. The expression levels of Kv1.5 in primary cultured
PASMC
s and pulmonary artery smooth muscle from
IUGR
or control rats were evaluated with and without application of an miR‐206 inhibitor. Right ventricular systolic pressure, cell proliferation, luciferase reporter assay, and
I
K
v
were also calculated. We found increased expression of miR‐206 in resistance pulmonary arteries of
IUGR
rats at 12 weeks compared with newborns. Application of an miR‐206 inhibitor in vivo or in vitro increased expression of Kv1.5 α‐protein and
KCNA
5. Also, decreased right ventricular systolic pressure and cell proliferation were observed in
PASMC
s from 12‐week‐old control and
IUGR
rats after
CH
, while inhibitor did not significantly affect control and
IUGR
rats.
Conclusions
These results suggest that expression of Kv1.5 and 4‐aminopyridine (Kv channel special inhibitor)‐sensitive Kv current were correlated with the inhibition of miR‐206 in
PA
rings of
IUGR
‐
CH
rats and cultured
IUGR PASMC
s exposed to hypoxia. Thus, miR‐206 may be a trigger for induction of exaggerated CH–pulmonary artery hypertension of
IUGR
via Kv1.5.
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