The research team, led by investigators at the First Affiliated Hospital of Zhejiang University School of Medicine in Hangzhou, combined human transcriptomic data with mouse genetics and single-cell sequencing to trace the role of Angptl2 in influenza-associated pulmonary fibrosis. Angptl2 is a multifunctional secreted protein produced abundantly by endothelial cells, the cells that line blood vessels, and it is already known to participate in inflammation and tissue remodeling. The new work positions it as a molecular bridge between viral damage to the pulmonary vasculature and the aberrant wound-healing response that produces fibrosis.

To establish the clinical relevance of Angptl2, the researchers performed transcriptome sequencing on bronchoalveolar lavage samples obtained from patients with influenza-associated pulmonary fibrosis and compared them with samples from non-fibrotic controls. The analysis revealed that Angptl2 expression was significantly elevated in the fibrotic patients, providing the first indication that this endothelial-associated factor is upregulated in the human disease context. This human finding then served as the starting point for a series of mechanistic experiments in animal and cell models.

In the laboratory, the team established a murine model of pulmonary fibrosis induced by H1N1 influenza virus, recapitulating the progression from acute viral injury to chronic fibrotic remodeling. Bulk transcriptome sequencing and single-cell RNA sequencing of fibrotic lung tissue confirmed that Angptl2 expression rises during disease development, with the increase concentrated particularly in endothelial cells. The single-cell analysis allowed the researchers to map which cell populations expressed the molecule and how its expression correlated with the emergence of fibrotic pathology, strengthening the case that the vascular compartment is an active participant rather than a passive bystander.

The most striking result came from genetic loss-of-function experiments. When the researchers studied mice lacking Angptl2, fibrosis in the influenza model was significantly attenuated. The lungs of Angptl2-deficient animals showed reduced deposition of extracellular matrix and preserved tissue architecture compared with their wild-type counterparts. Single-cell profiling of these protected mice revealed an expansion of a specific endothelial subpopulation marked by expression of Rgs2, a regulator of G-protein signaling. The authors interpret this Rgs2-positive population as a protective endothelial state, suggesting that Angptl2 normally suppresses this resilient phenotype and that its absence allows the vasculature to resist fibrotic transformation.

Mechanistically, the study dissects how Angptl2 promotes fibrosis at the cellular level. The researchers found that Angptl2 binds to the α5β1 integrin receptor on endothelial cells, triggering intracellular signaling through the MAPK and PI3K-AKT pathways. These cascades are well-known drivers of cell fate changes and survival, and in this context they push endothelial cells toward endothelial-to-mesenchymal transition, or EndMT. During EndMT, endothelial cells lose their characteristic markers, such as VE-cadherin, and acquire mesenchymal features, including expression of α-smooth muscle actin. Cells undergoing this transition secrete extracellular matrix components and contribute directly to the fibrotic burden of the lung.

The investigation did not stop at EndMT. Using transwell co-culture experiments, in which endothelial cells and fibroblasts are grown in shared medium but kept physically separated, the team demonstrated that endothelial cells undergoing Angptl2-driven EndMT secrete endothelin-1 (EDN1), a potent vasoactive peptide. This secreted EDN1 acts on neighboring fibroblasts, activating the NF-κB signaling pathway within them and converting them into an activated, matrix-producing state. The result is a two-step amplification loop: Angptl2 first transforms endothelial cells into mesenchymal-like matrix producers, and those transformed cells then recruit and activate fibroblasts through EDN1 signaling, compounding the accumulation of extracellular matrix and accelerating fibrotic progression.

Technically, the study is notable for the way it integrates multiple layers of evidence. Co-immunoprecipitation experiments supported the physical interaction between Angptl2 and the α5β1 integrin receptor, while pathway enrichment analyses of the sequencing data, including gene set enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway mapping, pointed to MAPK and PI3K-AKT signaling as downstream mediators. Hydroxyproline assays, which quantify collagen content in lung tissue, provided biochemical confirmation of the reduced fibrotic burden in Angptl2-deficient mice. The combination of human lavage fluid sequencing, a viral induction model, conditional genetics, single-cell transcriptomics, and in vitro co-culture gives the findings a level of triangulation that individual approaches alone could not achieve.

The clinical implications are considerable. Pulmonary fibrosis following viral respiratory infection, including influenza and by extension other viral pneumonias, currently has limited therapeutic options, and antiviral treatment does not address the downstream fibrotic remodeling that determines long-term lung function. If the Angptl2–α5β1 integrin–EndMT–EDN1 axis proves conserved in human disease beyond the lavage fluid expression data, it offers several potential points of intervention: blocking Angptl2 binding to its integrin receptor, inhibiting the downstream kinase pathways, or antagonizing EDN1 signaling, for which pharmacological tools already exist in the cardiovascular field. The expansion of the Rgs2-positive endothelial subpopulation in protected mice also suggests that promoting this protective vascular state could become a therapeutic goal in its own right.

As with any translational study, important questions remain before these findings can shape patient care. The mouse model uses H1N1 virus under controlled laboratory conditions, and the degree to which the Angptl2 pathway drives fibrosis in diverse human viral infections will require validation in larger patient cohorts with longitudinal sampling. Dosing, timing, and safety of any Angptl2-targeted intervention would need to be established, particularly since Angptl2 has documented roles in vascular biology elsewhere in the body. Nevertheless, by identifying a specific endothelial molecule that connects viral injury, endothelial-to-mesenchymal transition, and fibroblast activation through EDN1 signaling, the study provides a mechanistic framework for post-viral lung fibrosis and a concrete set of molecular targets for the development of antifibrotic therapies.

Subject of Research: The role of endothelial Angptl2 signaling in influenza-associated pulmonary fibrosis

Article Title: Endothelial Angptl2 orchestrates influenza-associated pulmonary fibrosis via EndMT and EDN1-mediated fibroblast activation

Article References: Liu, C., Bao, J., Ni, J., Yu, F., Hu, X., Mao, Z., Huang, M., Han, D., Zhang, D., Shen, Y., Qu, W., Xu, Y., Chen, W., Wang, Q., Chen, X., Wang, R., Zheng, S., & Chen, Y. (2026). Endothelial Angptl2 orchestrates influenza-associated pulmonary fibrosis via EndMT and EDN1-mediated fibroblast activation. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08922-4

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08922-4

Keywords: influenza, pulmonary fibrosis, Angptl2, endothelial dysfunction, EndMT, endothelin-1, fibroblast activation, H1N1, single-cell RNA sequencing, extracellular matrix, NF-κB, Rgs2