Vascular endothelial growth factor, or VEGF-A, has a complicated reputation in lung biology. The factor was originally discovered as vascular permeability factor, a molecule secreted by tumor cells that made blood vessels leak fluid at an alarming rate. In the lung, that leakiness is precisely the problem in acute lung injury: when the endothelial lining of pulmonary microvessels becomes permeable, protein-rich fluid floods the airspaces, oxygen exchange collapses, and patients may require mechanical ventilation to survive. Earlier clinical studies had found elevated VEGF in the airspaces of patients with respiratory distress syndrome, and researchers have long debated whether the growth factor is a culprit driving vascular leak or, paradoxically, a repair signal that helps the damaged endothelium recover. The new findings suggest that part of the confusion may have arisen because investigators were measuring a family of molecules with opposite effects as if it were a single entity.

The key to that complexity lies in alternative splicing, the process by which a single gene yields multiple protein versions. In the final stretch of the VEGF-A gene, two different sets of terminal exons can be stitched onto the coding sequence. One choice produces the classical pro-angiogenic isoforms, exemplified by VEGF165a, which bind the receptor VEGFR2 on endothelial cells and trigger the signaling cascades that make vessels grow and leak. The alternative choice produces the so-called b-variants, including VEGF165b, which differ in just six amino acids at the carboxyl terminus. That subtle change, first characterized by researchers studying kidney and cancer biology in the early 2000s, is enough to render the variant weakly angiogenic and poorly permeability-inducing, while still allowing it to occupy the same receptor. The b-isoforms therefore behave as natural antagonists of their pro-angiogenic siblings, competing for receptor binding without delivering the same intracellular message.

The Guangzhou-led team began by asking whether this splice balance is disturbed in human lung injury. Analyzing blood samples from patients, they found that the circulating ratio of VEGF165b to total VEGF-A was significantly reduced in acute lung injury, and that the lower the proportion of the protective variant, the more severe the disease. That inverse correlation, reported alongside ethical approval from the First Affiliated Hospital of Guangzhou Medical University and Zhujiang Hospital of Southern Medical University, provided the first hint that a relative deficiency of VEGF165b might accompany, and possibly contribute to, the vascular catastrophe of respiratory distress syndrome. Correlation alone cannot establish causation, so the investigators turned to experimental models in which the relationship could be tested directly.

In mice, the researchers induced acute lung injury with lipopolysaccharide, the inflammatory toxin derived from bacterial cell walls that mimics Gram-negative sepsis, one of the most common triggers of the human syndrome. When the animals received exogenous VEGF165b, the consequences of the insult were markedly blunted: pulmonary edema diminished, inflammatory infiltration of the lung tissue decreased, and overall measures of injury improved. The converse experiment proved equally telling. When the team neutralized endogenous VEGF165b with antibodies, leaving the pro-inflammatory isoforms to act unopposed, lung damage became worse. Together, these gain-of-function and loss-of-function results established the splice variant as a genuine endogenous protector rather than a passive bystander, and they identified the VEGF165b-to-total-VEGF ratio as a candidate biomarker for tracking disease severity.

The mechanistic core of the study explains how a single splice decision can translate into barrier protection at the molecular level. Using human microvascular endothelial cells, human pulmonary artery endothelial cells, and primary pulmonary microvascular endothelial cells, the researchers showed that VEGF165b acts as a competitive antagonist at VEGFR2, selectively blocking the phosphorylation of the receptor at tyrosine 1175, a docking site whose activation is known to be essential for the permeability response. With that phosphorylation event suppressed, the downstream PI3K/AKT/eNOS pathway, which normally drives nitric oxide production and vessel relaxation during vascular leak, was quieted. The team traced the consequences further downstream to the Src kinase and the adherens junction protein VE-cadherin, the molecular glue that holds endothelial cells together. When Src phosphorylates VE-cadherin, the junctions loosen and fluid escapes; by preventing the upstream signal, VEGF165b reduced VE-cadherin phosphorylation and thereby kept the endothelial barrier intact.

Intriguingly, the protective variant does not stop at junctional reinforcement. Through RNA sequencing and network analysis of the signaling hubs affected by VEGF165b, the investigators found that the variant also suppresses the chemokine CCL2, also known as monocyte chemoattractant protein 1. CCL2 is a potent recruiter of circulating monocytes, and its reduction translated into a second, distinct anti-inflammatory mechanism: fewer monocytes adhered to the endothelial surface, limiting the wave of inflammatory cells that normally amplifies tissue damage in acute lung injury. The authors describe this as a dual mode of action, in which VEGF165b simultaneously strengthens the physical wall of the microvasculature and dampens the cellular inflammatory assault against it. Such a combination is rare among candidate therapies, which typically address either leakiness or inflammation but rarely both.

The findings also reframe a long-running therapeutic debate. Several anti-VEGF strategies, including the monoclonal antibody bevacizumab, have been explored for severe COVID-19 and other causes of pulmonary edema on the logic that blocking VEGF should reduce vascular leak. But blanket VEGF blockade carries well-documented risks, including hypertension, proteinuria, and thromboembolism, precisely because the growth factor performs essential maintenance roles in healthy vessels. The splice-variant view offers a more surgical alternative: rather than eliminating VEGF signaling altogether, one could in principle restore the balance between pro-permeability and anti-permeability isoforms, either by administering recombinant VEGF165b, which has already been tested as an anti-cancer agent in animal models, or by shifting the splicing machinery toward the protective variant. The study’s demonstration that neutralizing VEGF165b worsens injury adds a note of caution for any therapy that removes this natural brake indiscriminately.

As with any preclinical advance, the road from mouse models and cell cultures to the intensive care unit is long. The patient data establish an association between a low VEGF165b fraction and disease severity, but clinical trials will be needed to determine whether replenishing the variant improves outcomes, at what dose, and at what stage of illness. Questions also remain about how the splicing balance is regulated in the acutely inflamed lung, and whether splicing factors such as the SRSF family, which other studies have implicated in acute lung injury, could serve as drug targets. Nevertheless, the conceptual payoff is substantial. The work reveals that vascular homeostasis in the lung depends on the critical equilibrium of VEGF splice variants, positions VEGF165b as both a biomarker and a potential therapeutic agent for acute lung injury and respiratory distress syndrome, and offers a new strategy for treating vascular barrier dysfunction in critical lung disease, one of the most stubborn unsolved problems in modern critical care medicine.

Subject of Research: The role of the VEGF-A splice variant VEGF165b in protecting against acute lung injury by antagonizing VEGF165a/VEGFR2 signaling

Article Title: VEGF165b attenuates LPS-induced acute lung injury via antagonizing the VEGF165a/VEGFR2 signaling pathway

Article References: Deng, J., Wang, X., Wu, Z., Bai, Q., Luo, Q., Zhou, L., Yao, Y., Wang, H., Zhong, K., Liu, H., Chen, X., & Wang, T. (2026). VEGF165b attenuates LPS-induced acute lung injury via antagonizing the VEGF165a/VEGFR2 signaling pathway. Angiogenesis, 29(4), Article 75. https://doi.org/10.1007/s10456-026-10090-4

Image Credits: AI Generated

DOI: 10.1007/s10456-026-10090-4

Keywords: acute lung injury, ARDS, VEGF165b, VEGFR2, vascular permeability, endothelial barrier, alternative splicing, VE-cadherin, CCL2, lipopolysaccharide, angiogenesis, pulmonary edema

The research, led by Anna Biedritzky and Michael Koeppen at University Hospital of Tuebingen in Germany, focused on a membrane-bound enzyme called ADAM17, short for A Disintegrin and Metalloproteinase 17. This protease is known to cleave, or shed, the outer portions of a wide range of molecules sitting on the cell surface, including adhesion proteins and cytokine receptors. By snipping these molecules, ADAM17 can fundamentally change how immune cells interact with blood vessels and how inflammatory signals propagate through tissue. What remained poorly understood was how much of the lung damage in ARDS could be attributed specifically to the version of ADAM17 produced by endothelial cells, the thin layer of cells lining the pulmonary microvasculature.

To answer this question, the team engineered mice in which the ADAM17 gene could be selectively deleted in endothelial cells using the Cre/loxP system, crossing mice carrying loxP-flanked ADAM17 alleles with Tie2-Cre driver animals. When these knockout mice and their normal littermates inhaled lipopolysaccharide, a bacterial endotoxin that triggers acute lung inflammation, the difference was striking. Three hours after exposure, total lung ADAM17 messenger RNA in the knockout animals was reduced by 77.5 percent compared with controls, demonstrating that endothelial cells are the dominant source of this protease in the inflamed lung. Flow cytometry confirmed that ADAM17 surface expression dropped on pulmonary endothelial cells while remaining intact on neutrophils and platelets, validating the specificity of the genetic deletion.

The most dramatic consequences appeared at the endothelial barrier itself. In control mice, LPS exposure caused the characteristic hallmarks of ARDS-like injury: thickening of the alveolar septa, gaps between endothelial cells, and protein-rich fluid pouring into the airspaces. In the knockout mice, lung architecture was substantially preserved. The researchers traced this protection to the maintenance of junctional integrity. Surface expression of JAM-A, a junctional adhesion molecule that redistributes during inflammation to permit leukocyte passage, was markedly altered in the absence of endothelial ADAM17. Crucially, the tight junction proteins ZO-1, occludin, and claudin-5, along with the adherens junction protein VE-cadherin, were all preserved at higher levels in the knockout animals, both in vivo and in cultured human endothelial and epithelial cells treated with ADAM17 inhibitors.

Functional measurements confirmed what the microscopy suggested. Using the Evans blue extravasation assay, in which a dye bound to albumin leaks out of vessels only when the barrier fails, the team showed that knockout lungs accumulated significantly less dye six hours after LPS challenge, the known peak of vascular leakage in this model. Total protein in bronchoalveolar lavage fluid, an indirect indicator of alveolar-capillary permeability, was also significantly lower in the knockout group. According to the authors, this represents the first direct demonstration of reduced Evans blue extravasation in this endothelial-specific ADAM17 knockout model, providing functional confirmation of a barrier-protective phenotype that earlier work had inferred mainly from histology and lavage protein measurements.

The study also resolved a long-standing question about where neutrophils get stuck when ADAM17 is missing. Rather than simply counting cells in the whole lung, the researchers used a compartment-specific flow cytometry approach, tagging neutrophils still inside the pulmonary vasculature with an intravenously injected antibody before tissue collection. This allowed them to distinguish intravascular, endothelial-adherent, interstitial, and intra-alveolar neutrophils. The results were revealing: knockout mice had similar numbers of circulating neutrophils as controls, but significantly more neutrophils retained at the endothelial surface and significantly fewer in the interstitium and alveolar space. The retained neutrophils showed elevated surface expression of the adhesion molecules CD162, also known as PSGL-1, and CD49d, an integrin subunit, consistent with a failure to complete the transmigration program.

Complementary experiments in a Transwell system, in which human neutrophils migrate across an endothelial-epithelial barrier along a chemotactic gradient of fMLP, reinforced this interpretation. Pharmacological inhibition of ADAM17 with TAPI-1, or dual inhibition of ADAM17 and ADAM10 with GW280264X, significantly reduced neutrophil transmigration, attenuated myeloperoxidase release, and lowered expression of the transmigration-associated molecules CD11b and JAM-A on the cells that did cross. Together, the in vivo and in vitro data suggest that endothelial ADAM17 does not control the initial adhesion of neutrophils to the vessel wall but rather their passage through it, coordinating shedding events that permit immune cells to squeeze between junctional complexes.

Beyond the physical barrier, the study uncovered a selective signaling role for the endothelial protease. Gene expression analysis three hours after LPS inhalation showed that deletion of endothelial ADAM17 selectively dampened two proinflammatory cascades: the TNF receptor 1 pathway, with reduced downstream NF-kappaB, JNK, TRADD, and CREB transcripts, and the interleukin-6 receptor pathway, with reduced JAK1 and STAT3 expression. In contrast, the TLR4 pathway, the primary sensor for bacterial endotoxin, was activated to the same degree in knockout and control mice, and immunostaining located TLR4 on endothelial cells, epithelial cells, and infiltrating neutrophils in both genotypes. The maturation and trafficking machinery for ADAM17 itself, involving iRhom2, AT1R, and iTAP, was likewise unaffected, indicating that the enzyme’s influence operates through its shedding substrates rather than through its own regulation.

The downstream consequences for the alveolar inflammatory milieu were substantial. Bronchoalveolar lavage fluid from knockout mice contained significantly less TNF-alpha, less soluble CD62L, less myeloperoxidase, and less neutrophil elastase, while levels of the anti-inflammatory cytokine IL-10 were higher, indicating a shift toward a resolving, less tissue-destructive environment. Pharmacological inhibition largely reproduced the genetic phenotype: TAPI-1 reduced interstitial neutrophil accumulation, GW280264X reduced both interstitial and alveolar accumulation, and both inhibitors preserved VE-cadherin expression, reduced chemokine CXCL2/3 release, and limited Evans blue leakage. Dual inhibition even caused neutrophils to pile up at the endothelium, mirroring the genetic knockout and pointing to cooperative roles for ADAM17 and ADAM10 in the transmigration cascade.

The authors are careful to note the translational caveats. In this study, inhibitors were given one hour before the LPS challenge, a standard target-validation design, so whether ADAM17 blockade helps after lung injury has already begun remains to be tested. Because ADAM17 has a broad substrate repertoire with physiological functions throughout the body, the authors suggest that future therapies may need to be temporally restricted, endothelial-targeted, locally delivered, or substrate-selective to minimize systemic side effects. Even with these limitations, the convergence of endothelial-specific genetic deletion and differential pharmacological inhibition makes a compelling case that ADAM17 on the pulmonary endothelium acts as a central inflammatory amplifier in acute lung injury, coordinating neutrophil trafficking, junctional destabilization, vascular leakage, and cytokine signaling. For a syndrome with mortality approaching forty percent and few options beyond supportive care, a druggable molecular chokepoint on the vessel wall is exactly the kind of target the field has been searching for.

Subject of Research: The role of endothelial ADAM17 in neutrophil migration and microvascular permeability during acute lung inflammation

Article Title: Endothelial ADAM17 facilitates neutrophil migration and pulmonary microvascular permeability in acute lung inflammation

Article References: Biedritzky, A., Kleinmaier, C., Fuhr, A., Herrmann, L. M., Ngamsri, K.-C., Konrad, F., & Koeppen, M. (2026). Endothelial ADAM17 facilitates neutrophil migration and pulmonary microvascular permeability in acute lung inflammation. Journal of Biomedical Science, 33(1), Article 91. https://doi.org/10.1186/s12929-026-01290-7

Image Credits: AI Generated

DOI: 10.1186/s12929-026-01290-7

Keywords: ARDS, ADAM17, endothelial barrier, neutrophil migration, acute lung injury, vascular permeability, TNF-alpha, IL-6 signaling, JAM-A, VE-cadherin, LPS, pulmonary inflammation

The study, published in the journal Angiogenesis, focuses on a long-standing puzzle in cancer biology: how tumors recruit and remodel blood vessels to sustain their growth. Tumors cannot enlarge beyond a few millimeters without recruiting new vasculature, a process known as tumor angiogenesis. The vessels that form inside tumors are typically abnormal — leaky, tortuously branched, and poorly covered by supportive pericyte cells — which creates hypoxic, acidic conditions that paradoxically stimulate even more angiogenic signalling, most notably through vascular endothelial growth factor, or VEGF, and its receptor VEGFR2. The new work reveals that Epac1 sits at a central junction of this process, coordinating both the chemical VEGF signals and the mechanical forces that shape tumor vessel formation.

Epac1, encoded by the gene RAPGEF3, is a guanine nucleotide exchange factor activated by the intracellular messenger cyclic AMP. It exists in two isoforms, but only Epac1 is expressed in endothelial cells, where it participates in regulating junctional dynamics and cell polarity. To determine whether Epac1 matters in tumor angiogenesis specifically, the team first analyzed publicly available single-cell RNA sequencing data from human primary melanomas and healthy human skin. They found that RAPGEF3 expression was markedly enriched in the endothelial cells of melanoma tissue compared with the endothelium of healthy skin, and that the gene was predominantly active in vascular rather than lymphatic endothelial cells. This human evidence suggested that the protein might be a genuine feature of the tumor vasculature rather than an artifact of experimental models.

The researchers then turned to mouse models. In mice lacking Epac1 throughout the body, subcutaneously implanted B16F10 melanoma cells still formed palpable tumors, but growth slowed dramatically after day fourteen — precisely the stage at which vascularization becomes the limiting factor for tumor expansion. By day eighteen, tumors in the knockout animals were roughly half the size of those in normal mice, and staining for the endothelial marker CD31 revealed a significantly smaller vascular area within them. Because global deletion could not distinguish effects in blood vessel cells from effects in other stromal cells, the team generated a second mouse line in which Epac1 could be deleted selectively in endothelial cells using a tamoxifen-inducible Cre system. The result was the same: reduced tumor volume and reduced vascularization, confirming that the endothelial supply of Epac1 itself drives melanoma growth.

To understand the molecular mechanism, the researchers isolated tumor endothelial cells from the melanomas and performed whole-transcriptome sequencing. In the Epac1-deficient vessels, gene ontology analysis showed broad downregulation of angiogenesis-associated pathways, including sprouting angiogenesis, endothelial cell migration, and proliferation. Key pro-angiogenic genes such as Kdr (which encodes VEGFR2), Angpt1, Hif1a, Dll1, and Dll4 were all reduced. Strikingly, the analysis also revealed suppressed expression of canonical target genes of the transcriptional co-activators YAP and TAZ — including Ccn1, Ccn2, and Ankrd1 — pointing to a previously unknown connection between Epac1 and the Hippo signalling pathway in tumor vessels.

YAP and TAZ are mechanosensitive transcriptional regulators that act as major effectors of the Hippo pathway. Their activity depends less on how much protein is present and more on where the protein resides: when they translocate into the nucleus, they partner with TEAD-family transcription factors to switch on genes that promote cell proliferation, migration, and survival. In the Epac1-deficient endothelial cells, the researchers found that total YAP and TAZ protein levels were unchanged, but nuclear localization was significantly reduced, and TEAD-dependent reporter activity was markedly diminished. A parallel experiment using a selective pharmacological inhibitor of Epac1’s enzymatic activity in human umbilical vein endothelial cells produced the same suppression of YAP/TAZ target gene expression, confirming that the catalytic function of the protein is required to maintain this transcriptional program.

The team then traced how Epac1 links VEGF signalling to YAP/TAZ activation. In control endothelial cells, VEGF stimulation robustly induced expression of Vegfr2 and Ccn2, activated the small GTPase RhoA, and promoted phosphorylation of myosin light chain 2, a key downstream target of the RhoA effector kinase ROCK. In Epac1-deficient cells, all of these responses were blunted or abolished. Pharmacological inhibition of RhoA with C3 transferase reduced TEAD-driven transcription and suppressed VEGF-induced Ccn2 expression, while VEGF-driven nuclear translocation of YAP and TAZ in human endothelial cells was fully prevented by RhoA inhibition. Together, these experiments establish a signalling chain running from Epac1 through VEGFR2, RhoA, and the actin cytoskeleton to the nucleus, where YAP and TAZ execute their pro-angiogenic gene program.

Perhaps the most striking findings concerned mechanosensing — the ability of endothelial cells to respond to physical forces such as blood flow. Tumor vessels experience disturbed, oscillatory flow patterns that promote pro-angiogenic signalling and metastasis. Using an in vitro system that applies oscillatory shear stress to endothelial monolayers, the researchers showed that control cells aligned themselves with the direction of flow, whereas Epac1-deficient cells completely failed to do so. Under the same conditions, oscillatory shear stress normally increases the interaction between VE-cadherin, the junctional adhesion protein, and VEGFR2 — a partnership thought to form part of the endothelial mechanosensory complex. Proximity ligation assays revealed that this interaction was abolished in Epac1-deficient cells, as was shear-induced phosphorylation of VE-cadherin at tyrosine 658, an essential modification for mechanosensing, and the shear-induced nuclear accumulation of YAP and TAZ. When the researchers reintroduced Epac1 into the knockout cells using lentiviral vectors, VEGFR2 and Ccn2 expression, VEGF responses, and flow-induced alignment were all rescued, confirming the specificity of the effect.

The study also carries an important nuance about Epac1’s role in vascular biology. Previous work by the same group and others has shown that Epac1 is dispensable during physiological angiogenesis — the retinal vascular area of Epac1-deficient mice at postnatal day five is comparable to that of wild-type animals — yet pathological neovascularization in oxygen-induced retinopathy is significantly reduced without the protein. The new melanoma data fit this pattern: endogenous endothelial Epac1 appears to be largely irrelevant for normal vascular maintenance but becomes functionally indispensable in pathological settings characterized by excessive VEGF signalling and altered mechanical cues. This context-dependence is encouraging from a therapeutic standpoint, because it suggests that drugs targeting Epac1 might impair tumor vessel growth while sparing the normal vasculature, potentially reducing the side effects that complicate current anti-angiogenic therapies.

The authors caution that their study used melanoma as the tumor model, and that the prominent upregulation of Epac1 in tumor endothelium and its consequences for tumor growth may not generalize to all cancer types. Nevertheless, the identification of Epac1 as a central modulator that integrates VEGF signalling, RhoA-dependent cytoskeletal dynamics, YAP/TAZ transcription, and flow mechanosensing provides the most complete mechanistic picture to date of how a single endothelial protein can orchestrate pathological tumor vascularization. With Epac inhibitors already under investigation for other cancers, the prospect of starving melanomas by dismantling the molecular machinery of their blood vessels has moved a tangible step closer to the clinic.

Subject of Research: The role of endothelial Epac1 in regulating VEGFR2 and YAP/TAZ signalling during melanoma angiogenesis

Article Title: Endothelial Epac1 facilitates YAP/TAZ controlled melanoma growth and angiogenesis

Article References: Wibowo, Y. C., Ma, N., Ren, Y., Cordero, J., Gahn, J., Chen, Z., Levay, M., Ola, R., Feng, Y., Dobreva, G., Langer, H., Wieland, T., Vettel, C., & Jansen, S. (2026). Endothelial Epac1 facilitates YAP/TAZ controlled melanoma growth and angiogenesis. Angiogenesis, 29(4), Article 72. https://doi.org/10.1007/s10456-026-10080-6

Image Credits: AI Generated

DOI: 10.1007/s10456-026-10080-6

Keywords: Epac1, melanoma, angiogenesis, tumor endothelial cells, VEGFR2, YAP/TAZ, Hippo signalling, RhoA, mechanotransduction, VE-cadherin, VEGF, skin cancer

The research, led by Yingying Zhu, Chun Jiang, Xiuhui He, Xiang Gao, and corresponding author Zhengxuan Jiang of the Department of Ophthalmology at The Second Affiliated Hospital of Anhui Medical University, describes a previously underappreciated signaling chain that connects the metabolic chaos of diabetes to the physical collapse of the retinal endothelial barrier. At the heart of the discovery is histone lactylation, a relatively recently identified epigenetic mark in which lactate-derived lactyl groups are chemically attached to lysine residues on histone tails. Rather than being an inert byproduct of metabolism, lactate in this context acts as a signaling molecule that reshapes which genes are switched on inside retinal blood vessel cells.

To dissect the mechanism, the team assembled evidence from multiple complementary systems. They examined human epiretinal membranes and fibrovascular membranes obtained from patients with proliferative diabetic retinopathy, retinal tissue from diabetic rats, and retinal endothelial cells grown under diabetic-like conditions. Across all of these models, a consistent pattern emerged: where lactate accumulated, protein lactylation rose, and one particular mark—lactylation at lysine 9 of histone H3, abbreviated H3K9la—stood out as prominently elevated under diabetic conditions. This convergence across human tissue, animal models, and cultured cells gave the finding a robustness that single-model studies often lack.

The critical question was what H3K9 lactylation actually does inside these endothelial cells. Histone modifications of this kind generally work by altering the physical state of chromatin, the complex of DNA and protein that packages the genome. When specific histone residues are acetylated or lactylated, the chromatin at nearby genes tends to loosen, granting the transcriptional machinery access and boosting gene expression. The researchers found that lactate-driven H3K9la became enriched at the promoter region of the PTK2 gene, which encodes focal adhesion kinase, a well-known regulator of cell adhesion, migration, and survival. With the promoter epigenetically opened up, PTK2 transcription increased, and levels of the phosphorylated, active form of the kinase climbed in parallel.

From there, the story moves from the nucleus to the cytoskeleton. Activated PTK2 was found to associate with FMNL2, a formin-family protein that governs the assembly of actin filaments, and this association was linked to increased tyrosine phosphorylation of FMNL2 itself. The consequence was a cascade of cytoskeletal remodeling inside the endothelial cells: the internal scaffolding of the cells reorganized in a way that destabilized VE-cadherin, the adhesive molecule that stitching neighboring endothelial cells together at adherens junctions. When VE-cadherin junctions falter, the endothelial sheet loses its seals, permeability rises, and fluid and proteins leak across the barrier. In the retina, that leakage translates directly into macular edema and progressive vision impairment.

What makes this axis scientifically compelling is that it forges a direct line from metabolism to cell structure through epigenetics. Diabetic tissue is known to be lactate-rich, a product of altered glucose metabolism and hypoxic stress. The study shows that this excess lactate does not merely fuel inflammation or oxidative damage indirectly; it physically marks the chromatin of barrier-regulating genes, amplifies a kinase–formin signaling module, and dismantles the junctions that hold the retinal vasculature together. In effect, a metabolic byproduct of diabetes becomes an epigenetic instruction that tells blood vessel cells to let go of each other.

Just as importantly, the research demonstrates that the damage is not irreversible in experimental settings. The team showed that pharmacologically reducing lactate production, inhibiting the catalytic activity of CBP/p300—the histone acetyltransferase enzymes responsible for writing lactylation marks—blocking PTK2 activity, or knocking down FMNL2 all attenuated endothelial barrier defects and reduced retinal vascular leakage. Each of these interventions targets a different rung on the same ladder, and the fact that several independent points of disruption produce protective effects strengthens the causal interpretation of the pathway and opens multiple potential angles for therapy.

The therapeutic implications are considerable. Existing treatments for diabetic retinopathy, such as anti-VEGF injections and laser photocoagulation, address downstream consequences of vascular dysfunction rather than the metabolic and epigenetic drivers of barrier failure. If the lactate–H3K9la–PTK2–FMNL2 axis can be safely modulated in patients—for example, by limiting lactate accumulation, tuning histone lactylation, or inhibiting focal adhesion kinase signaling locally in the eye—clinicians might one day intervene earlier in the disease process, before irreversible vascular damage takes hold. PTK2 inhibitors already exist in oncology research, and CBP/p300 catalytic inhibitors are under active investigation in multiple fields, meaning that repurposing strategies could accelerate translation.

The study also adds to a fast-growing body of literature on lactylation as a regulatory modification. Since histone lactylation was first described as a link between cellular metabolism and gene regulation, researchers have implicated it in macrophage polarization, tumor biology, fibrosis, and neural inflammation. The new work extends this framework to the vascular endothelium of the eye, suggesting that lactylation may be a general mechanism by which metabolically stressed tissues lose barrier integrity. Given that barrier failure is central to conditions ranging from sepsis to diabetic kidney disease, the conceptual reach of these findings may extend well beyond ophthalmology.

Caveats remain, as they always do at this stage of research. The pharmacological interventions were tested in experimental and preclinical systems, and the leap from rat retinas and cultured endothelial cells to human therapy will require careful validation, dosing studies, and safety assessment. Human tissue samples from proliferative diabetic retinopathy show the molecular signature, but they represent an advanced stage of disease; whether earlier interventions along this axis prevent progression is a question for future longitudinal work. Still, the identification of a defined metabolic–epigenetic–signaling pathway underlying inner blood–retinal barrier breakdown represents a genuine conceptual advance, one that reframes diabetic retinopathy not simply as a disease of damaged vessels, but as a disease of miswritten chromatin in the cells that guard the eye.

Subject of Research: Lactate-induced H3K9 histone lactylation disrupting the inner blood–retinal barrier via the PTK2–FMNL2 axis in diabetic retinopathy

Article Title: Lactate-induced H3K9 lactylation disrupts the inner blood–retinal barrier by activating the PTK2–FMNL2 axis in diabetic retinopathy

Article References: Zhu, Y., Jiang, C., He, X., Gao, X., & Jiang, Z. (2026). Lactate-induced H3K9 lactylation disrupts the inner blood–retinal barrier by activating the PTK2–FMNL2 axis in diabetic retinopathy. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06448-y

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06448-y

Keywords: diabetic retinopathy, inner blood–retinal barrier, histone lactylation, H3K9la, lactate, PTK2, FMNL2, VE-cadherin, endothelial permeability, focal adhesion signaling, epigenetics, retinal vascular leakage