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

Enter RGS2, or regulator of G-protein signaling 2, a protein that has fascinated cardiovascular physiologists for more than two decades. RGS2 acts as a negative regulator of Gq-coupled receptors, and chief among its targets is the angiotensin II type 1 receptor, or AT1R, the receptor through which angiotensin II executes many of its pressor and remodeling effects. Mice engineered to lack RGS2 throughout the body develop severe hypertension and prolonged vasoconstrictor signaling, and reduced RGS2 expression has been documented in hypertensive patients, where it correlates with exaggerated calcium mobilization and ERK1/2 phosphorylation in response to angiotensin II. RGS2 is also abundantly expressed in myeloid cells, which raises an intriguing paradox: if immune cells promote hypertension and RGS2 restrains angiotensin II signaling, should removing RGS2 specifically from myeloid cells unleash worsened hypertensive disease?

A team led by Nakagawa and colleagues set out to answer precisely that question. Using an elegant conditional knockout strategy, they generated mice in which RGS2 was selectively ablated in myeloid cells, a model designated RGS2 LysM-KO, and then challenged these animals with chronic angiotensin II infusion. The expectation, shared by the investigators themselves and by much of the field, was that loss of the AT1R brake in macrophages and related cells would amplify inflammatory signaling and thereby exacerbate hypertension and cardiovascular-renal injury.

The results defied those expectations. Across every measure the researchers examined, the myeloid-specific RGS2 knockout mice behaved essentially like their normal counterparts. Blood pressure responses to chronic angiotensin II were indistinguishable between the groups. Cardiac and renal damage, typically hallmarks of sustained pressor challenge, did not differ. Vascular dysfunction was unchanged, and inflammatory profiles failed to reveal any meaningful divergence attributable to the loss of myeloid RGS2. The authors concluded that myeloid RGS2 is not involved in angiotensin II-induced hypertension or cardiovascular-renal organ damage, a finding with significant conceptual implications.

Perhaps the most important implication is what the study says about the devastating hypertension of whole-body RGS2 deficiency. If deleting the protein in immune cells accomplishes nothing, then the severe, damaging hypertension seen when RGS2 is absent everywhere must be driven exclusively by altered RGS2 signaling in vascular and renal epithelial tissues rather than by the immune system. The brake that matters, in other words, is the one applied within the blood vessel wall and the kidney tubule, not the one applied inside infiltrating macrophages. This reallocation of responsibility helps sharpen where therapeutic efforts to modulate RGS2 signaling should be aimed.

Writing in a linked commentary in the same journal, Lorenzo A. Calò, Martina Cacciapuoti, and Paul A. Davis place these murine findings in a striking human context. Their laboratory has long studied Gitelman’s and Bartter’s syndromes, rare genetic tubulopathies caused by defects in specific kidney transporters and ion channels. These disorders are, in a sense, the mirror image of hypertension: they represent human models of endogenous angiotensin II signaling antagonism. Patients with Gitelman’s or Bartter’s syndrome display marked activation of the renin-angiotensin-aldosterone system, with high circulating levels of both angiotensin II and aldosterone, yet despite this hormonal surge they present with hypotension or normotension rather than hypertension.

The clinical paradox deepens on closer inspection. Beyond their low blood pressure, patients with these syndromes show hyporesponsiveness to pressor agents and display activation of antiatherosclerotic and antiremodeling defenses. Their vascular biology features reduced Rho kinase signaling, increased nitric oxide bioavailability, and diminished oxidative stress and oxidative stress-related signaling, all in the face of elevated angiotensin II. Something powerful is damping down the signaling that angiotensin II normally delivers through the AT1 receptor, and the commentary authors argue that RGS2 is a central player in this endogenous antagonism.

The cellular evidence they have accumulated is compelling. In fibroblasts derived from patients with Gitelman’s and Bartter’s syndromes, both RGS2 RNA and protein abundance are increased compared with cells from healthy normotensive subjects. Functionally, this elevated RGS2 blunts angiotensin II signaling at multiple levels: it attenuates short-term signaling, including intracellular calcium release and the calcium-protein kinase C pathway in vascular smooth muscle cells, and it also dampens long-term proliferative and profibrotic responses that drive remodeling. Most tellingly, when the researchers silenced RGS2 in fibroblasts from these patients, the cells reverted to a hypertensive-like angiotensin II response, characterized by increased intracellular calcium release and ERK1/2 phosphorylation. In other words, removing the RGS2 brake in human cells restores the very signaling signature that defines hypertensive disease.

Taken together, the mouse knockout study and the human syndrome data demonstrate that RGS2 regulation of angiotensin II signaling through the Gq/AT1R axis, and its downstream consequences for hypertension and cardiovascular-renal remodeling, differ substantially depending on the level and the location of the RGS2 system being probed. A brake present in immune cells appears dispensable for pressor responses in mice, whereas abundant RGS2 in vascular cells of patients with inherited angiotensin signaling antagonism exerts profound hypotensive and antiremodeling effects. Context, cellular identity, and tissue distribution are everything. The findings caution against assuming that a regulatory protein implicated in immune-driven inflammation will necessarily shape blood pressure outcomes when manipulated within the immune compartment.

The commentary authors look forward to future work from the Nakagawa group addressing the major limitations acknowledged in the study, including the angiotensin II doses and time points employed and the need for more selective targeting methods for myeloid-specific ablation. Such refinements could reveal subtler roles for myeloid RGS2 that the current model missed, or they could further cement the conclusion that the vascular and renal epithelium are where RGS2 truly determines the course of hypertensive disease. Either way, the convergence of a clean genetic experiment in mice with mechanistic insights from rare human syndromes offers a unusually clear picture of how one small regulatory protein helps set the tone of the renin-angiotensin system, and why understanding where a molecule acts matters as much as knowing what it does.

Subject of Research: The role of RGS2 regulation of angiotensin II signaling in hypertension and cardiovascular-renal remodeling

Article Title: Although myeloid‐cell RGS2 knockout does not affect Ang II–induced hypertension/organ damage in mice, high RGS2 in Gitelman/Bartter syndromes—human models of endogenous Ang II signaling antagonism—is associated with hypotensive/antiremodeling effects

Article References: Calò, L. A., Cacciapuoti, M., & Davis, P. A. (2026). Although myeloid‐cell RGS2 knockout does not affect Ang II –induced hypertension/organ damage in mice, high RGS2 in Gitelman/Bartter syndromes—human models of endogenous Ang II signaling antagonism—is associated with hypotensive/antiremodeling effects. Physiological Reports, 14(18), Article e71110. https://doi.org/10.14814/phy2.71110

Image Credits: AI Generated

DOI: 10.14814/phy2.71110

Keywords: RGS2, angiotensin II, hypertension, myeloid cells, Gitelman syndrome, Bartter syndrome, AT1 receptor, blood pressure, vascular remodeling, G-protein signaling, Although, myeloid