Fetal pulmonary hypertension: dysregulated microRNA-34c-Notch1 axis contributes to impaired angiogenesis in an ovine model. Pediatr Res 2023 Feb;93(3):551-558
Date
06/19/2022Pubmed ID
35717485Pubmed Central ID
PMC9759620DOI
10.1038/s41390-022-02151-3Scopus ID
2-s2.0-85132167802 (requires institutional sign-in at Scopus site)Abstract
BACKGROUND: Persistent pulmonary hypertension of the newborn (PPHN) occurs when pulmonary vascular resistance (PVR) fails to decrease at birth. Decreased angiogenesis in the lung contributes to the persistence of high PVR at birth. MicroRNAs (miRNAs) regulate gene expression through transcript binding and degradation. They were implicated in dysregulated angiogenesis in cancer and cardiovascular disease.
METHODS: We investigated whether altered miRNA levels contribute to impaired angiogenesis in PPHN. We used a fetal lamb model of PPHN induced by prenatal ductus arteriosus constriction and sham ligation as controls. We performed RNA sequencing of pulmonary artery endothelial cells (PAECs) isolated from control and PPHN lambs.
RESULTS: We observed a differentially expressed miRNA profile in PPHN for organ development, cell-cell signaling, and cardiovascular function. MiR-34c was upregulated in PPHN PAECs compared to controls. Exogenous miR34c mimics decreased angiogenesis by control PAEC and anti-miR34c improved angiogenesis of PPHN PAEC in vitro. Notch1, a predicted target for miR-34c by bioinformatics, was decreased in PPHN PAECs, along with Notch1 downstream targets, Hey1 and Hes1. Exogenous miR-34c decreased Notch1 expression in control PAECs and anti-miR-34c restored Notch1 and Hes1 expression in PPHN PAECs.
CONCLUSION: We conclude that increased miR-34c in PPHN contributes to impaired angiogenesis by decreasing Notch1 expression in PAECs.
IMPACT: Adds a novel mechanism for the regulation of angiogenesis in persistent pulmonary hypertension of the newborn. Identifies non-coding RNAs that are involved in the altered angiogenesis in PPHN and thus the potential for future studies to identify links between known pathways regulating angiogenesis. Provides preliminary data to conduct studies targeting miR34c expression in vivo in animal models of pulmonary hypertension to identify the mechanistic role of miR34c in angiogenesis in the lung vasculature.
Author List
Mukherjee D, Rana U, Kriegel AJ, Liu P, Michalkiewicz T, Konduri GGAuthors
Girija Ganesh Konduri MD Chief, Professor in the Pediatrics department at Medical College of WisconsinAlison J. Kriegel PhD Associate Professor in the Physiology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsEndothelial Cells
Female
Humans
Hypertension, Pulmonary
Infant, Newborn
MicroRNAs
Persistent Fetal Circulation Syndrome
Pregnancy
Pulmonary Artery
Receptor, Notch1
Sheep
Sheep, Domestic
