ArticleLaboratory investigation; a journal of technical methods and pathology2014
Granzyme B releases vascular endothelial growth factor from extracellular matrix and induces vascular permeability.
Article in Laboratory investigation; a journal of technical methods and pathology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 51 citations in OpenAlex.
- Granzyme B in age-related macular degeneration: mechanistic insights and therapeutic perspectives.Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie · 2026Review
- Emerging roles of granzymes in neurodegeneration and neuroinflammation: mechanistic insights and therapeutic opportunities.Acta neuropathologica · 2026Review
- Granzyme B from mast cells contributes to choroidal neovascularization in a model of wet age-related macular degeneration.Frontiers in immunology · 2026Article
- Plasma inflammatory and angiogenic protein profiling of patients with sickle cell disease.British journal of haematology · 2025Article
- Association Between Plasma Granzyme B Levels, Organ Failure, and 28-Day Mortality Prediction in Patients with Sepsis.Journal of clinical medicine · 2025Article
- Granzyme B and melittin in cancer immunotherapy: molecular mechanisms and therapeutic perspectives in head and neck cancers.Frontiers in immunology · 2025Review
- The pro-tumorigenic roles of granzyme B: mechanisms and therapeutic implications.Frontiers in immunology · 2025Review
- Granzyme B cleaves tenascin-C to release its C-terminal domain in rheumatoid arthritis.JCI insight · 2024Article
- Granzyme B degrades extracellular matrix and promotes inflammation and choroidal neovascularization.Angiogenesis · 2024Article
- Granzyme serine proteases in inflammation and rheumatic diseases.Nature reviews. Rheumatology · 2024Review
- Exploring the role of granzyme B in subretinal fibrosis of age-related macular degeneration.Frontiers in immunology · 2024Review
- The mRNA expression and secretion of granzyme B are up-regulated via the histamine H2 receptor in human CD4Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2023Article
- Critical role of mitogen-inducible gene 6 in restraining endothelial cell permeability to maintain vascular homeostasis.Journal of cell communication and signaling · 2023Article
- Contrasting behavior between the three human monocyte subsets in dengue pathophysiology.iScience · 2022Article
- Article
- Review
- Potential role of extracellular granzyme B in wet age-related macular degeneration and fuchs endothelial corneal dystrophy.Frontiers in pharmacology · 2022Review
- Type I interferon response and vascular alteration in chilblain-like lesions during the COVID-19 outbreak.The British journal of dermatology · 2021Observational
- A narrative review of changes in microvascular permeability after burn.Annals of translational medicine · 2021Review
- MAIT cell activation is associated with disease severity markers in acute hantavirus infection.Cell reports. Medicine · 2021Article
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
The formation of unstable, leaky neovessels underlies the pathogenesis of many chronic inflammatory diseases. Granzyme B (GZMB) is an immune-derived serine protease that accumulates in the extracellular matrix (ECM) during chronic inflammation and is capable of cleaving fibronectin (FN). Vascular endothelial growth factor (VEGF) is a potent vascular permeabilizing agent that is sequestered in the ECM through its interaction with FN. As GZMB levels are elevated in chronic inflammatory diseases that are associated with increased vascular permeability, the role of GZMB in the regulation of VEGF bioavailability and vascular permeability were assessed. GZMB was added to either VEGF bound to FN or VEGF bound to endothelial cell (EC)-derived ECM. Supernatants containing released VEGF were assessed to determine VEGF activity by treating EC and evaluating VEGF receptor-2 (VEGFR2) phosphorylation. GZMB released VEGF from both FN and from EC-derived matrix, whereas GZMB inhibition prevented FN cleavage and VEGF release. GZMB-mediated VEGF release resulted in significant phosphorylation of VEGFR2. The role of GZMB-mediated VEGF release in altering vascular permeability was also assessed in vivo using Miles/Evans blue permeability assay. GZMB induced a significant VEGF-dependent increase in vascular permeability in vivo that was reduced in the presence of an anti-VEGF-neutralizing antibody. Inflammatory-mediated vascular leakage was also assessed in GZMB-KO mice using a delayed-type hypersensitivity model. GZMB-KO mice exhibited reduced microvascular leakage compared with C57\B6 controls. GZMB increases vascular permeability in part through the proteolytic release of ECM-sequestered VEGF, leading to VEGFR2 activation and increased vascular permeability in vivo. These findings present a novel role for GZMB as a modulator of vascular response during chronic inflammation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.