Format

Send to

Choose Destination
Anesthesiology. 2018 Feb;128(2):361-374. doi: 10.1097/ALN.0000000000001907.

Vasculotide, an Angiopoietin-1 Mimetic, Restores Microcirculatory Perfusion and Microvascular Leakage and Decreases Fluid Resuscitation Requirements in Hemorrhagic Shock.

Author information

1
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.).

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.

PMID:
28968277
DOI:
10.1097/ALN.0000000000001907
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center