MiR-126a-5p is involved in the hypoxia-induced endothelial-to-mesenchymal transition of neonatal pulmonary hypertension

Abstract

Persistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome characterized by increased medial and adventitial thickness of the lung vasculature. The underlying mechanisms that regulate the cell phenotype alteration during PPHN remodeling are largely unknown. We randomly selected newborn rats that were exposed to hypoxia (10-12%) or room air for 2 weeks and used a microarray to identify the lung tissue microRNAs (miRNAs) involved in PPHN progression. The role of a key miRNA that affects the endothelial-to-mesenchymal transition (EndMT) in primary cultured rat pulmonary microvascular endothelial cells (RPMECs) was investigated. The expression of miR-126a-5p was elevated in the PPHN model according to microarray analysis. The relative expression of miR-126a-5p in RPMECs increased when they were exposed to hypoxia (P<0.05), consistent with the microarray results. Pecam1 expression decreased, whereas alpha-smooth muscle actin (α-SMA) increased in the hypoxic RPMECs. Knockdown of miR-126a-5p in RPMECs followed by treatment with hypoxia for 48 h resulted in a significant increase in the expression of Pecam1 and a reduction in α-SMA expression, with a simultaneous increase in PI3K (p85β) and phosphorylation of AKT at serine 473 compared with the negative control. Finally, the circulating miR-126a-5p concentration was upregulated in the PPHN model compared with healthy neonates. We concluded that hypoxia changed the cell homeostasis and that miR-126a-5p was upregulated in PPHN, which is partly responsible for hypoxia-induced EndMT. The mechanism underlying the upregulation of miR-126a-5p by hypoxia probably acts through the p85-β/p-AKT pathway.

Endothelial‐to‐mesenchymal transition in cardiovascular diseases: Developmental signaling pathways gone awry

“…Such crosstalk between hypoxia and TGF‐β signaling mechanisms can also be regulated by the expression of different miRNAs. For example, in hypoxia‐induced persistent pulmonary hypertension of the newborn (PPHN), a cardiac syndrome that can potentially affect a considerable number of neonates, elevated expression of miR‐126a‐5p, which inhibits TGF‐β signaling, was detected in a small set of serum samples of PPHN patients (Xu et al, ).…”

Temporal transcriptome analysis suggest modulation of multiple pathways and gene network involved in cell-cell interaction during early phase of high altitude exposure

“…Along with it cell-cell adhesion CAM's are involved in the transmission of signals across cell membrane [25]. It is reported that continuous hypobaric hypoxia cause altered expression of junctional protein complex of vascular endothelial cells [26,27]. As evident from our data gene transcripts like integrin ITGAV, ITGB2, ITGB7, ITGA4 and ITGA2; in cell adhesion molecule, focal adhesion and extracellular matrix receptor interaction, involvement of collagens COL6A3, COL6A2, claudins CLDN5 and other cell adhesion molecules like, ICAM3, CADM1, CDH2, CD58, ACTB, TLNN1, FLNA, ACTG1, LAMA5, PARVB, MYLK all are upregulated during initial time point in Kyrgyz suggesting modulation of cytoskeleton dynamics as a part of acclimatization to overcome hypobaric hypoxia.…”

MicroRNAs as critical regulators of the endothelial to mesenchymal transition in vascular biology

“…On the contrary, several miRNAs have the capacity to promote EndMT by directly targeting molecules associated with inhibition of EndMT ( 45 – 49 ). For example, miR-21 expression increased during TGF-β-induced EndMT in HUVECs and inhibition of miR-21 has been shown to partially prevent TGF-β-induced-EndMT.…”

“…Concomitantly, decreased expression of PECAM-1 and increased expression of α-SMA in the hypoxic RPMECs was observed. Finally, it was found that inhibition of miR-126a-5p ameliorates hypoxia-induced EndMT ( 49 ). The EndMT-related miRNAs and target genes are summarized in Table 1 and Fig.…”

“…These results suggest that the EndMT is an attractive prospective target with regard to prevention and treatment of many diseases. Indeed, the EndMT plays an essential role during development ( 52 ) and can also contribute to postnatal pathologies associated with many diseases such as fibrosis, neointima formation, diabetic complications, heterotopic ossification, Kawasaki disease and pulmonary arterial hypertension ( 11 , 24 , 25 , 27 , 28 , 38 , 42 – 46 , 48 , 49 , 53 ). Given that EndMT is closely involved in multiple diseases, the blocking of EndMT may represent a useful strategy for implementation in the treatment plans developed to combat human diseases.…”