High glucose‐mediated loss of cell surface heparan sulfate proteoglycan impairs the endothelial shear stress response

Brower, Jeremy; Targovnik, Jerome; Caplan, Michael R.; Massia, Stephen P.

doi:10.1002/cm.20430

Cited by 28 publications

(16 citation statements)

References 20 publications

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“…In vitro models of hyperglycemia associated with diabetes are characterized by loss of HS and of FSS mechanotransduction, most notably the loss of elongation of ECs in the direction of shear (133) and the phosphorylation of eNOS in response to FSS (134). The observations that with diabetes, atherosclerosis is distributed more uniformly in arteries rather than limited to the typical atherogenic regions (regions of low shear or disturbed flow) near bifurcations and curvatures (135) and that vasodilation is altered (136) suggest that there is something fundamentally different in the mechanosensing apparatus of ECs during disease and may be explained in part by alterations in GCX.…”

Section: Pathophysiological Functions Of the Glycocalyxmentioning

confidence: 99%

Mechanosensing at the Vascular Interface

Tarbell

Simon

Curry

2014

Annu. Rev. Biomed. Eng.

160

129

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Mammals are endowed with a complex set of mechanisms that sense mechanical forces imparted by blood flow to endothelial cells (ECs), smooth muscle cells, and circulating blood cells to elicit biochemical responses through a process referred to as mechanotransduction. These biochemical responses are critical for a host of other responses, including regulation of blood pressure, control of vascular permeability for maintaining adequate perfusion of tissues, and control of leukocyte recruitment during immunosurveillance and inflammation. This review focuses on the role of the endothelial surface proteoglycan/glycoprotein layer—the glycocalyx (GCX)—that lines all blood vessel walls and is an agent in mechanotransduction and the modulation of blood cell interactions with the EC surface. We first discuss the biochemical composition and ultrastructure of the GCX, highlighting recent developments that reveal gaps in our understanding of the relationship between composition and spatial organization. We then consider the roles of the GCX in mechanotransduction and in vascular permeability control and review the prominent interaction of plasma borne sphingosine-1 phosphate (S1P), which has been shown to regulate both the composition of the GCX and the endothelial junctions. Finally, we consider the association of GCX degradation with inflammation and vascular disease and end with a final section on future research directions.

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Section: Pathophysiological Functions Of the Glycocalyxmentioning

confidence: 99%

Mechanosensing at the Vascular Interface

Tarbell

Simon

Curry

2014

Annu. Rev. Biomed. Eng.

160

129

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“…Hyperglycaemia that is linked with diabetes has been shown in vitro to lead to loss of HS and associated shear stress-induced phosphorylation of endothelial nitric oxide synthase (eNOS) [55] and elongation of ECs in the direction of shear [56] that are caused by mechanotransduction mediated by HS. In diabetic individuals, it has been observed that atherosclerosis is distributed more uniformly in arteries, not following the typical association with regions of low shear or disturbed flow near bifurcations and curvatures [57].…”

Section: Diabetes and Kidney Diseasementioning

confidence: 99%

The glycocalyx and its significance in human medicine

2016

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Cells are covered by a surface layer of glycans that is referred to as the 'glycocalyx'. In this review, we focus on the role of the glycocalyx in vascular diseases (atherosclerosis, stroke, hypertension, kidney disease and sepsis) and cancer. The glycocalyx and its principal glycosaminoglycans [heparan sulphate (HS) and hyaluronic acid (HA)] and core proteins (syndecans and glypicans) are degraded in vascular diseases, leading to a breakdown of the vascular permeability barrier, enhanced access of leucocytes to the arterial intima that propagate inflammation and alteration of endothelial mechanotransduction mechanisms that protect against disease. By contrast, the glycocalyx on cancer cells is generally robust, promoting integrin clustering and growth factor signalling, and mechanotransduction of interstitial flow shear stress that is elevated in tumours to upregulate matrix metalloproteinase release which enhances cell motility and metastasis. HS and HA are consistently elevated on cancer cells and are associated with tumour growth and metastasis. Later, we will review the agents that might be used to enhance or protect the glycocalyx to combat vascular disease, as well as a different set of compounds that can degrade the cancer cell glycocalyx to suppress cell growth and metastasis. It is clear that what is beneficial for either vascular disease or cancer will not be so for the other. The overarching conclusions are that (i) the importance of the glycocalyx in human medicine is only beginning to be recognized, and (ii) more detailed studies of glycocalyx involvement in vascular diseases and cancer will lead to novel treatment modalities.

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“…Increase in diameter (mm) during exposures of the test segment lumen (n=6) to hyperinsulinaemic blood (insulin) 0.229±0.116, compared with hyperinsulinaemic blood plus 250 μg/ml l-NAME (insulin + l-NAME) 0.041±0.026, p=0.0313, Wilcoxon matched-pairs signed-rank test NO synthase by the mechanotransducer, the vascular glycocalyx. 7,10,[25][26][27] Comparable timings are difficult to obtain from published in-vitro data in umbilical vein cells, compounded by the fact that endothelial cells in vitro do not express a complete glycocalyx. 28 We have therefore confined ourselves to testing whether arterial dilatation caused by intraluminal hyperinsulinaemia is NO dependent.…”

Section: Discussionmentioning

confidence: 92%

The responses of the iliac artery to insulin: direct delayed nitric oxide-mediated dilatation

O'Hora

Markos

Wainwright

et al. 2011

Diabetes & Vascular Disease

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T he aim of the study was to determine the effect of insulin on a conduit artery. In a closed-off test segment of iliac artery in vivo in anaethetised pigs, pressure was kept constant. During the first 10 minutes of exposure to hyperinsulinaemic blood, the test segment diameter was 3.63±0.64 mm (mean ± SD). Dilatation occurred after 10 minutes when the test segment diameter increased to 3.80±0.62 mm (mean ± SD), p=0.0006, n=10. The increase in diameter with the vehicle for insulin in blood was -0.0775±0.116 mm (mean ± SD, n=6) and with hyperinsulin in blood was 0.165±0.124 mm (mean ± SD, n=10), p=0.0024. Dilatation with hyperinsulin was 0.229±0.116 mm (mean ± SD) versus insulin plus 250 µg/ml of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester hydrochloride (L-NAME), 0.041±0.026 mm (mean ± SD), p=0.0313, n=6. No evidence of arterial constriction was observed in the presence of L-NAME. We conclude that insulin has a direct relaxing effect on the smooth muscle in the wall of conduit artery, mediated by nitric oxide. Br J Diabetes Vasc Dis 2011;11:130-136.

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High glucose‐mediated loss of cell surface heparan sulfate proteoglycan impairs the endothelial shear stress response

Cited by 28 publications

References 20 publications

Mechanosensing at the Vascular Interface

Mechanosensing at the Vascular Interface

The glycocalyx and its significance in human medicine

The responses of the iliac artery to insulin: direct delayed nitric oxide-mediated dilatation

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