Razuprotafib Does Not Improve Microcirculatory Perfusion Disturbances nor Renal Edema in Rats on Extracorporeal Circulation
Abstract
1. Introduction
2. Results
2.1. ECC Disturbed Microcirculatory Perfusion
2.2. ECC Induced Edema in the Kidney, but Not in the Lung
2.3. Razuprotafib Suppressed the Increase in TNFα, but Increased Angiopoietin-2
2.4. Molecular Alterations in the Angiopoietin/Tie2 System
2.5. Razuprotafib Reduces Lung Injury Following ECC
3. Discussion
4. Materials and Methods
4.1. Experimental Set-Up
4.2. Anesthesia, Analgesia, and Surgical Preparation
4.3. Treatment with Razuprotazib, a Small-Molecule Inhibitor of VE-PTP
4.4. Extracorporeal Circulation
4.5. Cremaster Microcirculatory Perfusion
4.6. Renal and Pulmonary Edema
4.7. Vascular Leakage
4.8. Plasma Analyses
4.9. RNA Analyses
4.10. Histology
4.11. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ANOVA | analysis of variance |
ARDS | acute respiratory syndrome |
ARRIVE | animal research: reporting of in vivo experiments |
COVID19 | coronavirus disease 2019 |
CPB | cardiopulmonary bypass |
ECC | extracorporeal circulation |
ECG | electrocardiogram |
ECMO | extracorporeal membrane oxygenation |
FITC | fluorescein isothiocyanate |
HCO3− | bicarbonate |
ICAM-1 | intercellular adhesion molecule 1 |
ICU | intensive care unit |
IL-6 | interleukin-6 |
MAP | mean arterial pressure |
mRNA | messenger ribonucleic acid |
PaCO2 | carbon dioxide tension |
PaO2 | oxygen tension |
PaO2/FiO2 | ratio of arterial oxygen tension to fractional inspired oxygen |
PCR | polymerase chain reaction |
PPV | proportion of perfused vessels |
TNFα | tumor necrosis factor α |
VA-ECMO | venoarterial ECMO |
VE-cadherin | vascular endothelial cadherin |
VE-PTP | vascular endothelial protein tyrosine phosphatase |
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Control (n = 8) | ECC (n = 11) | ECC + Razuprotafib (n = 11) | |
---|---|---|---|
Kidney | |||
Interstitial edema | 0 [0–0] | 0 [0–0] | 0 [0–0] |
Tubular injury | 0 [0–0] | 0 [0–0] | 0 [0–0] |
Lung | |||
Perivascular edema | 2 [1–3] | 2 [2–3] | 2 [2–3] |
Alveolar edema | 0 [0–1] | 0 [0–0] | 0 [0–0] |
Neutrophil sequestration | 1 [0–1] | 1 [0–1] | 1 [1–1] |
Interstitial inflammation | 0 [0–0] | 1 [1–1] *** | 0 [0–1] # |
Hemorrhage | 0 [0–0] | 0 [0–0] | 0 [0–0] |
Thrombi | 0 [0–0] | 0 [0–0] | 0 [0–0] |
Gene | Assay ID | Encoded Protein |
---|---|---|
Tek | Rn01433337_m1 | Endothelial-specific receptor tyrosine kinase (Tie2) |
Tie1 | Rn01417182_m1 | Tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (Tie1) |
Ptprb | Rn01502973_m1 | Protein tyrosine phosphatase, receptor type, B (VE-PTP) |
Rplp0 | Rn00821065_g1 | 60S acidic ribosomal protein P0 (Arbp) |
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Dubelaar, D.P.C.; Volleman, C.; Phelp, P.G.; Ibelings, R.; Voorn, I.; Tuip-de Boer, A.M.; Polet, C.A.; Roelofs, J.J.; Vlaar, A.P.J.; van Meurs, M.; et al. Razuprotafib Does Not Improve Microcirculatory Perfusion Disturbances nor Renal Edema in Rats on Extracorporeal Circulation. Int. J. Mol. Sci. 2025, 26, 3000. https://doi.org/10.3390/ijms26073000
Dubelaar DPC, Volleman C, Phelp PG, Ibelings R, Voorn I, Tuip-de Boer AM, Polet CA, Roelofs JJ, Vlaar APJ, van Meurs M, et al. Razuprotafib Does Not Improve Microcirculatory Perfusion Disturbances nor Renal Edema in Rats on Extracorporeal Circulation. International Journal of Molecular Sciences. 2025; 26(7):3000. https://doi.org/10.3390/ijms26073000
Chicago/Turabian StyleDubelaar, Dionne P. C., Carolien Volleman, Philippa G. Phelp, Roselique Ibelings, Iris Voorn, Anita M. Tuip-de Boer, Chantal A. Polet, Joris J. Roelofs, Alexander P. J. Vlaar, Matijs van Meurs, and et al. 2025. "Razuprotafib Does Not Improve Microcirculatory Perfusion Disturbances nor Renal Edema in Rats on Extracorporeal Circulation" International Journal of Molecular Sciences 26, no. 7: 3000. https://doi.org/10.3390/ijms26073000
APA StyleDubelaar, D. P. C., Volleman, C., Phelp, P. G., Ibelings, R., Voorn, I., Tuip-de Boer, A. M., Polet, C. A., Roelofs, J. J., Vlaar, A. P. J., van Meurs, M., & van den Brom, C. E. (2025). Razuprotafib Does Not Improve Microcirculatory Perfusion Disturbances nor Renal Edema in Rats on Extracorporeal Circulation. International Journal of Molecular Sciences, 26(7), 3000. https://doi.org/10.3390/ijms26073000