Vasculotide, an angiopoietin-1 mimetic, reduces pulmonary vascular leakage and preserves microcirculatory perfusion during cardiopulmonary bypass in rats

Dekker, Nicole; Meurs, Matijs van; Leeuwen, Anoek L I van; Hofland, H.M.; Slyke, Paul Van; Vonk, Alexander B.A.; Boer, Christa; Brom, Charissa E. van den

doi:10.1016/j.bja.2018.05.049

Cited by 32 publications

(39 citation statements)

References 39 publications

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“…In contrast, no effect of CPB on total vessel density (TVD), small vessel density (SVD), or vessel density (VD) was observed. These observations are in line with recent experimental and theoretical insights [30,32,33], suggesting that CPB does not necessarily affect the absolute number of microvessels, but mainly impairs microcirculatory red blood cell flow patterns, as reflected by a reduced number of perfused vessels (PVD). CPBassociated factors such as hemodilution, contact activation, and the induction of a systemic inflammatory response are thought to impair microcirculatory perfusion by affecting both transport and diffusion of oxygen at the microvascular level.…”

Section: Discussionsupporting

confidence: 89%

Microcirculatory perfusion disturbances following cardiopulmonary bypass: a systematic review

Brom

Leeuwen

et al. 2020

Crit Care

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Background: Microcirculatory perfusion disturbances are associated with increased morbidity and mortality in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Technological advancements made it possible to monitor sublingual microcirculatory perfusion over time. The goal of this review is to provide an overview of the course of alterations in sublingual microcirculatory perfusion following CPB. The secondary goal is to identify which parameter of sublingual microcirculatory perfusion is most profoundly affected by CPB. Methods: PubMed and Embase databases were systematically searched according to PRISMA guidelines and as registered in PROSPERO. Studies that reported sublingual microcirculatory perfusion measurements before and after onset of CPB in adult patients undergoing cardiac surgery were included. The primary outcome was sublingual microcirculatory perfusion, represented by functional capillary density (FCD), perfused vessel density (PVD), total vessel density (TVD), proportion of perfused vessels (PPV), and microvascular flow index (MFI). Results: The search identified 277 studies, of which 19 fulfilled all eligibility criteria. Initiation of CPB had a profound effect on FCD, PVD, or PPV. Seventeen studies (89%) reported one or more of these parameters, and in 11 of those studies (65%), there was a significant decrease in these parameters during cardiac surgery; the other 6 studies (35%) reported no effect. In 29% of the studies, FCD, PVD, or PPV normalized by the end of cardiac surgery, and in 24% percent of the studies, this effect lasted at least 24 h. There was no clear effect of CPB on TVD and a mixed effect on MFI. Conclusion: CPB during cardiac surgery impaired sublingual microcirculatory perfusion as reflected by reduced FCD, PVD, and PPV. Four studies reported this effect at least 24 h after surgery. Further research is warranted to conclude on the duration of CPB-induced microcirculatory perfusion disturbances and the relationship with clinical outcome.

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Section: Discussionsupporting

confidence: 89%

Microcirculatory perfusion disturbances following cardiopulmonary bypass: a systematic review

Brom

Leeuwen

et al. 2020

Crit Care

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“…33 Moreover, it was shown recently that strategies aiming to preserve microcirculatory perfusion during CPB may require an additional direct action on endothelial cell receptors involved in barrier signaling. 17,34 Limitations of the Study A limitation of this study is that it was performed in a relatively small cohort with a single center design. Moreover, all microvascular parameters were measured sublingually as the sublingual microcirculatory network provides an easily accessible site to investigate changes in microcirculatory perfusion.…”

Section: Discussionmentioning

confidence: 99%

“…5 Capillary red blood cell concentration and perfused boundary region were automatically calculated using Glycocheck software (Glycocheck, Microvascular Health Solutions, Orem, UT). 16,17 The general idea is that the endothelial glycocalyx consists of an outer red blood cell permeable region and an inner red blood cell impermeable region. Degradation of endothelial glycocalyx layer results in increased red blood cell permeable region (perfused boundary region), which allows close contact of flowing blood cells with the vascular endothelium.…”

Section: Microcirculatory Perfusion and Glycocalyx Measurementsmentioning

confidence: 99%

Microvascular Alterations During Cardiac Surgery Using a Heparin or Phosphorylcholine-Coated Circuit

Dekker

Veerhoek

Leeuwen

et al. 2020

Journal of Cardiothoracic and Vascular Anesthesia

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Objective: Heparin biocompatible coating frequently is used to reduce inflammation and blood coagulation during cardiopulmonary bypass (CPB) in cardiac surgery. Whether heparin coating is protective or damaging to the vascular endothelium is unclear. The authors investigated whether heparin-coated (HC) circuits are associated with better preservation of microcirculatory perfusion and glycocalyx dimensions compared with nonheparin phosphorylcholine-coated (PC) circuits. Design: Prospective, randomized blinded study. Setting: Tertiary university hospital. Participants: A total of 26 adults undergoing elective coronary artery bypass graft surgery with CPB. Interventions: PC (n = 13) versus HC circuits (n = 13). Measurements and Main Results: Sublingual microcirculatory perfusion was measured before, during, and after CPB using sidestream dark field imaging and analyzed for perfused vessel density and perfused boundary region, an inverse parameter for glycocalyx dimensions. Onset of CPB was associated with an increase in perfused boundary region in the PC group that continued until the third postoperative day (2.0 § 0.2 to 2.5 § 0.2 mm; p = 0.018). This was paralleled by increased plasma syndecan-1 levels in the PC group. Contrastingly, both parameters remained unaltered in the HC group compared with baseline levels. CPB decreased perfused vessel density in both groups (CPB v pre-CPB: PC: 17 § 2 to 13 § 2 mm/mm 2 , p = 0.006; HC: 16 § 2 to 11 § 2 mm/mm 2 , p = 0.003) and remained equally altered in the first 3 postoperative days. Conclusion: The use of an HC circuit is associated with better preservation of the endothelial glycocalyx compared with PC circuits, whereas microcirculatory perfusion was disturbed equally in both groups. Hence, CPB-induced microcirculatory perfusion disturbances seem to be coating independent.

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“…Likewise, Tie2 signaling decreases vascular permeability by tightening intra-EC junctions; this effect is mediated by associations of Tie2 receptors on adjacent cells and reorganization of key adhesion molecule vascular endothelial-cadherin (VE-cadherin) complexes [ 82 ]. As examples of its critical role in regulating vascular permeability in health and disease, Tie2 activation reduces pulmonary vascular leakage during cardiopulmonary bypass in rats [ 83 ], reduces cerebrovascular permeability and stroke size in mouse models [ 84 ], and reduced renal vascular edema and transcapillary albumin flux is a mouse model of acute kidney injury [ 85 ].…”

Section: Areas Coveredmentioning

confidence: 99%

The Tie2 signaling pathway in retinal vascular diseases: a novel therapeutic target in the eye

et al. 2020

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Background Retinal vascular diseases such as neovascular age-related macular degeneration, diabetic retinopathy and/or diabetic macular edema, and retinal vein occlusion with macular edema—share several key pathophysiologic aspects including neovascularization, vascular permeability, and inflammation. The role of vascular endothelial growth factor (VEGF) in these processes, and the therapeutic benefits of VEGF inhibition, have been well characterized. Anti-VEGF therapy is highly effective for many patients but is not uniformly effective in all patients and imposes a significant treatment burden. More recently, the role of the Tie2 signaling pathway in the pathophysiology of retinal vascular diseases has been investigated, and the Tie2 pathway represents a novel therapeutic target for these conditions. Areas covered The index review describes the Tie2 pathway and its complementary role to the VEGF pathway in the angiogenesis cascade and will summarize studies of molecules in development to therapeutically modulate the Tie2 pathway in retinal vascular diseases. Conclusions Activation of the Tie2 pathway leads to downstream signaling that promotes vascular health and stability and decreases vascular permeability and inflammation. AXT107 is a collagen IV–derived synthetic peptide with a dual mechanism of action that involves suppression of VEGF signaling and activation of the Tie2 pathway; these actions are accomplished by AXT107 binding to and disrupting different integrin, leading to blockade of the VEGF receptor and rearrangement of cellular Tie2 rendering it susceptible to Ang2 agonism. Other Tie2 agonist compounds are also in development, including faricimab and razuprotafib. Tie2 activation only modestly impacts angiogenesis on its own but significantly potentiates VEGF suppression. Co-regulation of the VEGF and Tie2 signaling pathways has the potential to improve functional and structural outcomes in eyes with retinal vascular diseases.

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Vasculotide, an angiopoietin-1 mimetic, reduces pulmonary vascular leakage and preserves microcirculatory perfusion during cardiopulmonary bypass in rats

Cited by 32 publications

References 39 publications

Microcirculatory perfusion disturbances following cardiopulmonary bypass: a systematic review

Microcirculatory perfusion disturbances following cardiopulmonary bypass: a systematic review

Microvascular Alterations During Cardiac Surgery Using a Heparin or Phosphorylcholine-Coated Circuit

The Tie2 signaling pathway in retinal vascular diseases: a novel therapeutic target in the eye

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