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Cited by 127Angiogenesis and VEGF in CancerWound Healing and TreatmentsProtease and Inhibitor Mechanisms

Plasmin Modulates Vascular Endothelial Growth Factor-A-Mediated Angiogenesis during Wound Repair

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Roth, Detlev, Piekarek, Michael, Paulsson, Mats, Christ, Hildegard, Bloch, Wilhelm, Krieg, Thomas, Davidson, Jeffrey M., Eming, Sabine A.·2006·The American Journal of Pathology
DOI 10.2353/ajpath.2006.050372PMC PMC1606492
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Abstract

Plasmin-catalyzed cleavage of the vascular endothelial growth factor (VEGF)-A isoform VEGF165 results in loss of its carboxyl-terminal heparin-binding domain and significant loss in its bioactivity. Little is known about the in vivo significance of this process. To investigate the biological relevance of the protease sensitivity of VEGF165 in wound healing we assessed the activity of a VEGF165 mutant resistant to plasmin proteolysis (VEGF165(A111P)) in a genetic mouse model of impaired wound healing (db/db mouse). In the present study we demonstrate that in this mouse model plasmin activity is increased at the wound site. The stability of the mutant VEGF165 was substantially increased in wound tissue lysates in comparison to wild-type VEGF165, thus indicating a prolonged activity of the plasmin-resistant VEGF165 mutant. The db/db delayed healing phenotype could be reversed by topical application of wild-type VEGF165 or VEGF165(A111P). However, resistance of VEGF165 to plasmin cleavage resulted in the increased stability of vascular structures during the late phase of healing due to increased recruitment of perivascular cells and delayed and reduced endothelial cell apoptosis. Our data provide the first indication that plasmin-catalyzed cleavage regulates VEGF165-mediated angiogenesis in vivo. Inactivation of the plasmin cleavage site Arg110/Ala111 may preserve the biological function of VEGF165 in therapeutic angiogenesis under conditions in which proteases are highly active, such as wound repair and inflammation.

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  • VEGFA induction is a hallmark of inflammatory processes leading to wound healing.

    “Of note, VEGFA induction is a hallmark of inflammatory processes leading to wound healing81.”

    From Trisomy 21 causes changes in the circulating proteome indicative of chronic autoinflammation (2017) · cites this paper as [81]

    The wound-healing results report increased cellular infiltration and vascularized granulation tissue after VEGF165 treatment, and the Discussion links VEGF165 treatment to improved re-epithelialization (pages unavailable). These passages support a role for VEGF-A in wound repair, but they do not establish that endogenous VEGF-A induction is a hallmark of inflammatory processes leading to healing. (LLM, conf=0.84)

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Cited by

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Authors
Roth, D., Piekarek, M., Paulsson, M., Christ, H., Bloch, W., Krieg, T., Davidson, J. M., & Eming, S. A.
Affiliations
  • University of Cologne (DE)
  • United States Department of Veterans Affairs (US)
Corresponding author
Eming, Sabine A.
ORCID
Venue
The American Journal of Pathology
Publisher
Elsevier BV
Published
2006-02
Volume
168
Issue
2
Pages
670-684
ISSN
0002-9440 (ISSN-L)
DOI
10.2353/ajpath.2006.050372
PMC
PMC1606492
OpenAlex
W2075749165
Cited by
127
References
1
Citations by year
2026: 2 · 2025: 2 · 2024: 2 · 2023: 2 · 2022: 4 · 2021: 4 · 2020: 6 · 2019: 2 · 2018: 5 · 2017: 4 · 2016: 7 · 2015: 11 · 2014: 11 · 2013: 7 · 2012: 9
FWCI
3.95
Type
journal article
Language
en
Open access
Licence
Locations
  • American Journal Of Pathology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Deutsche Forschungsgemeinschaft (SFB 589, FOR 265)
  • European Commission (LSHB-CT-2005-512102)
  • U.S. Department of Veterans Affairs
  • National Institutes of Health (AG06528)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
  • Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
Keywords
plasmin, VEGF-A, VEGF165, angiogenesis, wound healing, proteolytic cleavage, heparin-binding domain, db/db mice, delayed wound healing, endothelial cell apoptosis, therapeutic angiogenesis, inflammation
MeSH terms
Animals, Cells, Cultured, Chlorocebus aethiops, Diabetes Mellitus, Type 2, Disease Models, Animal, Endothelium, Vascular, Fibrinolysin, Fibrinolytic Agents, Humans, Mice, Inbred C57BL, Mice, Mutant Strains, Phenotype, Umbilical Veins, Wound Healing, Mutagenesis, Site-Directed, Apoptosis, Neovascularization, Physiologic, COS Cells, Vascular Endothelial Growth Factor A, Mice

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