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Expression and Proteolysis of Vascular Endothelial Growth Factor is Increased in Chronic Wounds
Open accessAbstract
Degradation of angiogenic mediators might be an underlying cause of chronic wounds. To test this hypothesis, we evaluated the expression and integrity of vascular endothelial growth factor, a potent angiogenic mediator, and its receptors, Flt-1 and KDR, in chronic venous leg ulcerations. Immunohisto- chemical, in situ hybridization, and semiquantitative reverse transcriptase polymerase chain reaction analyses all indicate that expression of vascular endothelial growth factor is elevated in ulcerative tissue, with vascular endothelial growth factor mRNA being especially pronounced in the hyperplastic epithelium of the wound margin. Flt-1 and KDR protein and mRNA were detected in the papillary vessels in close vicinity to the lesional epithelium of chronic wounds. Although increased expression of vascular endothelial growth factor protein was detected in the epidermis, the intensity of this staining was weak compared with the epidermal staining in psoriatic lesions and compared with the strong vascular endothelial growth factor mRNA signal in chronic wounds and psoriasis. To analyze whether this apparent decrease in immunoreactivity could be the result of degradation of vascular endothelial growth factor by proteolytic activities from the wound environment, we examined the stability of recombinant vascular endothelial growth factor in wound fluid from chronic leg ulcers. As demonstrated by sodium dodecyl sulfate polyacrylamide gel electrophoresis, incubation of rVEGF165 with chronic, but not acute, wound fluid resulted in rapid proteolytic degradation of rVEGF165. Protease inhibitor studies indicate that serine proteases, such as plasmin, are involved in this degradation. Together, our data show that, although vascular endothelial growth factor expression is elevated in chronic wounds, increased proteolytic activity in this environment results in its degradation, which may contribute to an impaired wound healing response.
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“As a consequence, factors crucial for wound healing, e.g., the major proteinase inhibitors (e.g., α1-proteinase inhibitor and α2-macroglobulin), components of the provisional wound matrix (e.g., fibronectin and vitronectin), growth factors (e.g., PDGF, VEGF) are degraded or inactivated by proteolytic cleavage in chronic wounds [246, 247].”
From Transition from inflammation to proliferation: a critical step during wound healing (2016) · cites this paper as [247]
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“Last, in chronic wounds, there is a marked increase in serine proteases that degrades matrix components, including fibronectin, as well as various key growth factors, all of which are required for remodeling of the ECM and cell growth (38-41).”
From Wound repair and regeneration: Mechanisms, signaling, and translation (2014) · cites this paper as [41]
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Metadata
- Authors
- Lauer, G., Sollberg, S., Cole, M., Krieg, T., Eming, S. A., Flamme, I., Stürzebecher, J., & Mann, K.
- Affiliations
- University of Cologne (DE)
- Friedrich Schiller University Jena (DE)
- Max Planck Institute of Biochemistry (DE)
- Corresponding author
- Eming, Sabine A.
- Venue
- Journal of Investigative Dermatology
- Publisher
- Elsevier BV
- Published
- 2000-07
- Volume
- 115
- Issue
- 1
- Pages
- 12-18
- ISSN
- 0022-202X (ISSN-L)
- OpenAlex
- W2004127276
- Cited by
- 349
- References
- 43
- Citations by year
- 2026: 3 · 2025: 18 · 2024: 16 · 2023: 11 · 2022: 21 · 2021: 10 · 2020: 17 · 2019: 10 · 2018: 15 · 2017: 13 · 2016: 15 · 2015: 13 · 2014: 13 · 2013: 16 · 2012: 15
- FWCI
- 11.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Investigative Dermatology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Health Sciences › Medicine › Surgery › Wound Healing and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Keywords
- vascular endothelial growth factor, chronic wounds, chronic venous leg ulcers, proteolysis, VEGF receptors, Flt-1, KDR, serine protease, plasmin, wound fluid, delayed wound healing, psoriasis, angiogenic mediators
- MeSH terms
- Chronic Disease, Drug Stability, Exudates and Transudates, Fibrinolysin, Humans, Leg Ulcer, Lymphokines, Protease Inhibitors, Proto-Oncogene Proteins, Recombinant Proteins, RNA, Messenger, Wounds and Injuries, Up-Regulation, Gene Expression, Endothelial Growth Factors, Receptors, Growth Factor, Protein Isoforms, Receptor Protein-Tyrosine Kinases, Receptors, Vascular Endothelial Growth Factor, Vascular Endothelial Growth Factor Receptor-1, Vascular Endothelial Growth Factors, Vascular Endothelial Growth Factor A
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