Newly Published
Critical Care Medicine  |   October 2017
Vasculotide, an Angiopoietin-1 Mimetic, Restores Microcirculatory Perfusion and Microvascular Leakage and Decreases Fluid Resuscitation Requirements in Hemorrhagic Shock
Author Notes
  • From the Departments of Anesthesiology (M.T., A.L.I.v.L., C.B., C.E.v.d.B.), Physiology (M.T., A.L.I.v.L., C.E.v.d.B.), and Trauma Surgery (L.M.G.G.), VU University Medical Center, Amsterdam, The Netherlands; Departments of Pathology and Medical Biology (M.v.M.) and Critical Care (M.v.M.), University Medical Center Groningen, Groningen, The Netherlands; and Vasomune Therapeutics, Toronto, Ontario, Canada (P.V.S., V.H.).
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • Submitted for publication January 31, 2017. Accepted for publication August 21, 2017.
    Submitted for publication January 31, 2017. Accepted for publication August 21, 2017.×
  • Acknowledgments: The authors thank Nick J. Koning, M.Sc., and Tom Grandjean, B.Sc. (Department of Anesthesiology, VU University Medical Center, Amsterdam, The Netherlands), for their help with the set-up and execution of the animal experiments, as well as Dan J. Dumont, M.D., Ph.D. (Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada), for his advice on the molecular analysis of the angiopoietin/Tie2 system.
    Acknowledgments: The authors thank Nick J. Koning, M.Sc., and Tom Grandjean, B.Sc. (Department of Anesthesiology, VU University Medical Center, Amsterdam, The Netherlands), for their help with the set-up and execution of the animal experiments, as well as Dan J. Dumont, M.D., Ph.D. (Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada), for his advice on the molecular analysis of the angiopoietin/Tie2 system.×
  • Research Support: Supported by a Young Investigator Grant from the Dutch Society of Anesthesiology (NVA; Utrecht, The Netherlands; to M.v.M.) and a Research Project Grant 2016 from the European Society of Anesthesiology (Brussels, Belgium; to C.E.v.d.B.).
    Research Support: Supported by a Young Investigator Grant from the Dutch Society of Anesthesiology (NVA; Utrecht, The Netherlands; to M.v.M.) and a Research Project Grant 2016 from the European Society of Anesthesiology (Brussels, Belgium; to C.E.v.d.B.).×
  • Competing Interests: Dr. Van Slyke is listed as inventor on three patents related to vasculotide filed by Vasomune Therapeutics (Toronto, Ontario, Canada). The other authors declare no competing interests.
    Competing Interests: Dr. Van Slyke is listed as inventor on three patents related to vasculotide filed by Vasomune Therapeutics (Toronto, Ontario, Canada). The other authors declare no competing interests.×
  • Correspondence: Address correspondence to Dr. van den Brom: De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. c.vandenbrom@vumc.nl. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Critical Care Medicine / Critical Care / Renal and Urinary Systems / Electrolyte Balance
Critical Care Medicine   |   October 2017
Vasculotide, an Angiopoietin-1 Mimetic, Restores Microcirculatory Perfusion and Microvascular Leakage and Decreases Fluid Resuscitation Requirements in Hemorrhagic Shock
Anesthesiology Newly Published on October 5, 2017. doi:10.1097/ALN.0000000000001907
Anesthesiology Newly Published on October 5, 2017. doi:10.1097/ALN.0000000000001907
Abstract

Background: Microcirculatory dysfunction is associated with multiple organ failure and unfavorable patient outcome. We investigated whether therapeutically targeting the endothelial angiopoietin/Tie2 system preserves microvascular integrity during hemorrhagic shock.

Methods: Rats were treated with the angiopoietin-1 mimetic vasculotide and subjected to hemorrhagic shock and fluid resuscitation. Microcirculatory perfusion and leakage were assessed with intravital microscopy (n = 7 per group) and Evans blue dye extravasation (n = 8 per group), respectively. The angiopoietin/Tie2 system was studied at protein and RNA level in plasma, kidneys, and lungs.

Results: Hemorrhagic shock significantly reduced continuously perfused capillaries (7 ± 2 vs. 11 ± 2) and increased nonperfused vessels (9 ± 3 vs. 5 ± 2) during hemorrhagic shock, which could not be restored by fluid resuscitation. Hemorrhagic shock increased circulating angiopoietin-2 and soluble Tie2 significantly, which associated with microcirculatory perfusion disturbances. Hemorrhagic shock significantly decreased Tie2 gene expression in kidneys and lungs and induced microvascular leakage in kidneys (19.7 ± 11.3 vs. 5.2 ± 3.0 µg/g) and lungs (16.1 ± 7.0 vs. 8.6 ± 2.7 µg/g). Vasculotide had no effect on hemodynamics and microcirculatory perfusion during hemorrhagic shock but restored microcirculatory perfusion during fluid resuscitation. Interestingly, vasculotide attenuated microvascular leakage in lungs (10.1 ± 3.3 µg/g) and significantly reduced the required amount of volume supplementation (1.3 ± 1.4 vs. 2.8 ± 1.5 ml). Furthermore, vasculotide posttreatment was also able to restore microcirculatory perfusion during fluid resuscitation.

Conclusions: Targeting Tie2 restored microvascular leakage and microcirculatory perfusion and reduced fluid resuscitation requirements in an experimental model of hemorrhagic shock. Therefore, the angiopoietin/Tie2 system seems to be a promising target in restoring microvascular integrity and may reduce organ failure during hemorrhagic shock.