He Zhang, Sixie Zheng, Zheng Wang, Yingying Xiao, Yuqing Hu, Debao Li, Qing Cui, Chenxi Liu, Yiting Xue, Junhua Wu, Sijuan Sun, Lincai Ye
Affiliated Women and Children’s Hospital of Ningbo University. Shanghai Children’s Medical Center and Shanghai Jiao Tong University School of Medicine. Children’s Hospital of Fudan University and National Children’s Medical Center.
China
Cell and Bioscience
Cell Biosci 2025; 14:
DOI: 10.1186/s13578-025-01502-x
Abstract
Background: Increased pulmonary blood flow (IncPBF), one of the most important features of many children with congenital heart diseases, is well-known as a prerequisite for the induction of pulmonary arterial hypertension. However, due to the lack of neonatal mouse models of IncPBF, it remains largely unknown how IncPBF affects postnatal lung development.
Methods and results: A neonatal mouse model of IncPBF was created via abdominal aorta and inferior vena cava fistula microsurgery at postnatal day 7 (P7) and verified by abdominal ultrasound and cardiac ultrasound. Hematoxylin-eosin staining demonstrated that at P14, the number of alveoli was significantly reduced in the IncPBF group compared with the sham group. Immunostaining further confirmed the results, showing that the markers of alveoli type 1 (AT1), alveoli type 2 (AT2), and endothelial cells were significantly reduced in the IncPBF group compared with the sham group. Moreover, RNA-sequencing analysis demonstrated a substantial difference of gene expression profile between IncPBF and sham lungs, and many gene ontology terms or reactome enrichment that are associated with normal alveolar development and pulmonary function, such as angiogenesis, cell migration, and lipid metabolism, were downregulated. Mechanistically, suppression of Mfap5-positive myofibroblasts or Shh-Gli1 signaling could ameliorate IncPBF-induced alveolar hypoplasia.
Conclusions: IncPBF led to alveolar dysplasia during the early developmental stage, and a neonatal mouse model of IncPBF was successfully created. This study introduced a platform for understanding IncPBF-associated pediatric diseases.
Category
Class I. Pulmonary Hypertension Associated with Congenital Cardiovascular Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Pulmonary Vascular Pathology
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes