Dual Pharmacological Inhibition of Angiopoietin-2 and VEGF-A in Murine Experimental Sepsis.
Angiopoietin
Endothelium
Sepsis
Tie2
Vascular endothelial growth factor
Vascular leakage
Journal
Journal of vascular research
ISSN: 1423-0135
Titre abrégé: J Vasc Res
Pays: Switzerland
ID NLM: 9206092
Informations de publication
Date de publication:
2020
2020
Historique:
received:
02
09
2019
accepted:
30
09
2019
pubmed:
15
11
2019
medline:
10
9
2020
entrez:
15
11
2019
Statut:
ppublish
Résumé
Sepsis is a pathological host response to infection leading to vascular barrier breakdown due to elevated levels of angiopoietin-2 (Angpt-2) and vascular endothelial growth factor-A (VEGF-A). Here, we tested a novel heterodimeric bispecific monoclonal IgG1-cross antibody of Angpt-2 and VEGF - termed "A2V." Cecal ligation and puncture was used to induce murine polymicrobial sepsis. Organs and blood were harvested for fluorescence immunohistochemistry and RT-PCR, and survival was recorded. In vitro endothelial cells were stimulated with plasma from septic shock patients costimulated with A2V or IgG antibody followed by immunocytochemistry and real-time transendothelial electrical resistance. Septic mice treated with A2V had a reduced induction of the endothelial adhesion molecule ICAM-1, leading to a trend towards less transmigration of inflammatory cells (A2V: 42.2 ± 1.0 vs. IgG 48.5 ± 1.7 Gr-1+ cells/HPF, p = 0.08) and reduced tissue levels of inflammatory cytokines (e.g., IL-6 mRNA: A2V 9.4 ± 3.2 vs. IgG 83.9 ± 36.7-fold over control, p = 0.03). Endothelial permeability was improved in vivo and in vitro in stimulated endothelial cells with septic plasma. Survival was improved by 38% (p = 0.02). Dual inhibition of Angpt-2 and VEGF-A improves murine sepsis morbidity and mortality, making it a potential therapeutic against vascular barrier breakdown.
Sections du résumé
BACKGROUND
Sepsis is a pathological host response to infection leading to vascular barrier breakdown due to elevated levels of angiopoietin-2 (Angpt-2) and vascular endothelial growth factor-A (VEGF-A). Here, we tested a novel heterodimeric bispecific monoclonal IgG1-cross antibody of Angpt-2 and VEGF - termed "A2V."
METHODS
Cecal ligation and puncture was used to induce murine polymicrobial sepsis. Organs and blood were harvested for fluorescence immunohistochemistry and RT-PCR, and survival was recorded. In vitro endothelial cells were stimulated with plasma from septic shock patients costimulated with A2V or IgG antibody followed by immunocytochemistry and real-time transendothelial electrical resistance.
RESULTS
Septic mice treated with A2V had a reduced induction of the endothelial adhesion molecule ICAM-1, leading to a trend towards less transmigration of inflammatory cells (A2V: 42.2 ± 1.0 vs. IgG 48.5 ± 1.7 Gr-1+ cells/HPF, p = 0.08) and reduced tissue levels of inflammatory cytokines (e.g., IL-6 mRNA: A2V 9.4 ± 3.2 vs. IgG 83.9 ± 36.7-fold over control, p = 0.03). Endothelial permeability was improved in vivo and in vitro in stimulated endothelial cells with septic plasma. Survival was improved by 38% (p = 0.02).
CONCLUSION
Dual inhibition of Angpt-2 and VEGF-A improves murine sepsis morbidity and mortality, making it a potential therapeutic against vascular barrier breakdown.
Identifiants
pubmed: 31726451
pii: 000503787
doi: 10.1159/000503787
doi:
Substances chimiques
Angiopoietin-2
0
Vascular Endothelial Growth Factor A
0
Intercellular Adhesion Molecule-1
126547-89-5
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
34-45Informations de copyright
© 2019 S. Karger AG, Basel.