Heparin Impairs Glycocalyx Barrier Properties and Attenuates Shear Dependent Vasodilation in Mice

VanTeeffelen, Jurgen W. G. E.; Brands, Judith; Jansen, Carin; Spaan, Jos A. E.; Vink, Hans

doi:10.1161/hypertensionaha.107.089250

Cited by 74 publications

(113 citation statements)

References 45 publications

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“…This hypothesis fits with the study of Gritters et al, who previously demonstrated an effect of heparin during HD on proteoglycan-bound PF4 possibly due to LMWH-induced endothelial detachment [16]. VanTeeffelen et al showed in mice that a heparin challenge is associated with increased vascular leakage of dextrans and impaired arteriolar vasodilation during reactive hyperemia, suggesting that competitive binding of heparin to glycocalyx-associated proteins may affect glycocalyx barrier properties [29]. On the other hand, heparins were found to bind P-Selectin, and may thus play a protective role in the early process of leucocyte adhesion and thereby block the cascade of ESL alterations [30].…”

Section: Discussionsupporting

confidence: 88%

Effects of Ultrapure Hemodialysis and Low Molecular Weight Heparin on the Endothelial Surface Layer

et al. 2014

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Background: Chronic kidney disease patients show changes in the endothelial surface layer (ESL). Whether hemodialysis (HD) itself or low molecular weight heparins (LMWH) induce ESL alterations is unknown. Methods: We studied the ESL in 20 HD patients with Sidestream Dark Field Imaging [measuring perfused boundary region (PBR)] and measurement of ESL constituents in plasma during HD in 2 studies. LMWH was administered at the start of HD in study A, and 120 min after the start of HD in study B. Mean platelet volume (MPV) and platelet large cell ratio (P-LCR) were also measured. Results: Syndecan-1 increased significantly 30 min after LMWH administration. sP-Selectin increased 120 min after HD start, and MPV and P-LCR decreased significantly during HD. No significant changes of PBR, sE-Selectin, sICAM-1, or sVCAM-1 were perceived. Conclusions: HD caused a significant increase in Syndecan-1 without a change in PBR. The administration of LMWH appeared to precede the rise in Syndecan-1.

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Section: Discussionsupporting

confidence: 88%

Effects of Ultrapure Hemodialysis and Low Molecular Weight Heparin on the Endothelial Surface Layer

et al. 2014

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“…Biopsies were taken from the transplanted kidneys at 10 min after reperfusion, and P-selectin expression on peritubular capillary endothelium was assessed using a semiquantitative score: 0, no staining; 1, mild staining of some capillaries; 2, moderate staining of most peritubular capillaries; and 3, intense staining of all peritubular capillaries. (14,19,23,40). Glycocalyx loss in ischemically injured kidneys is therefore expected to result in reduced nitric oxide production, which has indeed been observed in human kidney transplantations with delayed graft function (20).…”

Section: Discussionmentioning

confidence: 92%

Acute ischemic injury to the renal microvasculature in human kidney transplantation

Snoeijs¹,

Vink²,

Voesten³

et al. 2010

American Journal of Physiology-Renal Physiology

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Increased understanding of the pathophysiology of ischemic acute kidney injury in renal transplantation may lead to novel therapies that improve early graft function. Therefore, we studied the renal microcirculation in ischemically injured kidneys from donors after cardiac death (DCD) and in living donor kidneys with minimal ischemia. During transplant surgery, peritubular capillaries were visualized by sidestream darkfield imaging. Despite a profound reduction in creatinine clearance, total renovascular resistance of DCD kidneys was similar to that of living donor kidneys. In contrast, renal microvascular perfusion in the early reperfusion period was 42% lower in DCD kidneys compared with living donor kidneys, which was accounted for by smaller blood vessel diameters in DCD kidneys. Furthermore, DCD kidneys were characterized by smaller red blood cell exclusion zones in peritubular capillaries and by greater production of syndecan-1 and heparan sulfate (main constituents of the endothelial glycocalyx) compared with living donor kidneys, providing strong evidence for glycocalyx degradation in these kidneys. We conclude that renal ischemia and reperfusion is associated with reduced capillary blood flow and loss of glycocalyx integrity. These findings form the basis for development of novel interventions to prevent ischemic acute kidney injury. ischemia-reperfusion injury; endothelial glycocalyx KIDNEY TRANSPLANTATION IS inevitably associated with ischemia and reperfusion injury. Depending on the severity of injury, 20 -80% of recipients of deceased donor kidneys require dialysis treatment in the first week after transplantation, which is referred to as delayed graft function (26). This condition complicates patient management and is associated with a 40% increased rate of graft loss in kidneys from donors after brain death (45). Liberal use of donations after cardiac death greatly expands the number of available donor kidneys and may even eliminate transplant waiting lists (37). However, kidneys from these donors suffer extensive ischemic injury from circulatory arrest until organ preservation, which almost invariably leads to delayed graft function after transplantation. More importantly, up to 15-25% of these kidneys will never regain function, unnecessarily exposing recipients to the risks of major surgery and immunological sensitization (43).Adequate reperfusion is essential for functional recovery of donor kidneys and prevents ongoing ischemic tissue injury after revascularization. In rodent models of ischemic acute kidney injury, it has been demonstrated that the peritubular microcirculation suffers endothelial injury and functional impairment after reperfusion (5, 44), which has recently been observed in humans as well (13,21,31). The endothelium is covered by the glycocalyx, a dynamic network of proteoglycans and glycoproteins that determines vascular permeability, transduces shear stress to the endothelium, and prevents interaction of leukocytes and platelets with the vascular wall (29). Loss of endothel...

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“…However, glycosaminoglycans at high concentrations in the circulation could also bind to plasma proteins that normally bind to the glycocalyx, leading to destabilization of a healthy glycocalyx. 82 Such complex and opposing effects might necessitate monitor ing of glycocalyx function before treatment with glycos aminoglycans so as to determine whether an individual will benefit.…”

Section: Glycosaminoglycansmentioning

confidence: 99%

The glycocalyx—linking albuminuria with renal and cardiovascular disease

2015

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Albuminuria is commonly used as a marker of kidney disease progression, but some evidence suggests that albuminuria also contributes to disease progression by inducing renal injury in specific disease conditions. Studies have confirmed that in patients with cardiovascular risk factors, such as diabetes and hypertension, endothelial damage drives progression of kidney disease and cardiovascular disease. A key mechanism that contributes to this process is the loss of the glycocalyx--a polysaccharide gel that lines the luminal endothelial surface and that normally acts as a barrier against albumin filtration. Degradation of the glycocalyx in response to endothelial activation can lead to albuminuria and subsequent renal and vascular inflammation, thus providing a pathophysiological framework for the clinical association of albuminuria with renal and cardiovascular disease progression. In this Review, we examine the likely mechanisms by which glycocalyx dysfunction contributes to kidney injury and explains the link between cardiovascular disease and albuminuria. Evidence suggests that glycocalyx dysfunction is reversible, suggesting that these mechanisms could be considered as therapeutic targets to prevent the progression of renal and cardiovascular disease. This possibility enables the use of existing drugs in new ways, provides an opportunity to develop novel therapies, and indicates that albuminuria should be reconsidered as an end point in clinical trials.

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Heparin Impairs Glycocalyx Barrier Properties and Attenuates Shear Dependent Vasodilation in Mice

Cited by 74 publications

References 45 publications

Effects of Ultrapure Hemodialysis and Low Molecular Weight Heparin on the Endothelial Surface Layer

Effects of Ultrapure Hemodialysis and Low Molecular Weight Heparin on the Endothelial Surface Layer

Acute ischemic injury to the renal microvasculature in human kidney transplantation

The glycocalyx—linking albuminuria with renal and cardiovascular disease

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