ORIGINAL RESEARCH article
Front. Immunol.
Sec. Inflammation
Neonatal Pulmonary Vascular Remodeling Induced by Increased Blood Flow Is Associated with an Antiviral-like Immune Signature
Sixie Zheng 1
Hao Li 1
She Siqi 1
依婷 薛 1
Debao Li 2
Jiapei Wang 3
Yuqing Hu 1
Jing Wang 1
Lincai Ye 1
1. Shanghai Children's Medical Center, Shanghai, China
2. Children's Hospital of Fudan University, Shanghai, China
3. Ningbo Women and Children's Hospital, Ningbo, China
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Abstract
Background: Approximately 70% of pediatric pulmonary arterial hypertension (PAH) is associated with congenital heart disease causing increased pulmonary blood flow (IPF). The developing neonatal lung is highly susceptible to hemodynamic stress, yet the direct causal link and mechanisms of neonatal IPF-induced pulmonary vascular remodeling remain poorly understood due to the lack of suitable animal models that recapitulate this critical developmental window. Methods: We established a novel neonatal mouse model of IPF by performing an aortocaval fistula (ACF) on postnatal day 7(P7). Pulmonary hemodynamics were assessed by ultrasound at P30. Vascular remodeling was evaluated through histology (H&E, α-SMA immunofluorescence) and molecular analysis of phenotypic markers (Spp1, Myh11). Transcriptomic profiling (RNA-seq) and pathway enrichment analysis were employed to uncover underlying mechanisms, with flow cytometry and immunosuppression (Cyclosporin A) and type I interferon receptor blocker (MAR1-5A3) used for functional validation. Results: The neonatal ACF model successfully induced a left-to-right shunt, resulting in significant IPF and right ventricular volume overload. IPF mice exhibited pronounced pulmonary small vessel remodeling, evidenced by increased α-SMA intensity, elevated synthetic-phenotype marker (Spp1) expression, and decreased contractile-phenotype marker (Myh11). Transcriptomic analysis revealed a dominant immune signature, with the most enriched pathways being antiviral and interferon-response related ( response to virus and IL-17 signaling). This was corroborated by a significant increase in pulmonary CD4+ and CD8+ T cells. Crucially, immunosuppressive treatment and type I interferon receptor blocker attenuated vascular remodeling. Conclusions: We provide the direct experimental evidence that neonatal IPF alone is sufficient to drive pulmonary small vessel remodeling. The process is fundamentally mediated by an activated immune response characterized by an antiviral-like signature, a mechanism distinct from those reported in classic adult PAH models. This novel model offers a critical platform for investigating the developmental-specific pathogenesis of pediatric PAH and bridging the translational "valley of death."
Summary
Keywords
Increased pulmonary blood flow, Left-to-right shunt, Lung, neonatal animal models, Pulmonary vascular remodeling
Received
04 January 2026
Accepted
17 February 2026
Copyright
© 2026 Zheng, Li, Siqi, 薛, Li, Wang, Hu, Wang and Ye. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Jiapei Wang; Yuqing Hu; Jing Wang; Lincai Ye
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