Endothelial Glycocalyx Hyaluronan

Wang, Gangqi; Tiemeier, Gesa L.; Berg, Bernard M. van den; Rabelink, Ton J.

doi:10.1016/j.ajpath.2019.07.022

Cited by 45 publications

(25 citation statements)

References 89 publications

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“…This manifests as increased levels of reactive oxygen species (ROS) (123,154) and iNOS (87) as well as increased surface levels of the integrin CD11b (155) and other molecules (see below). Increased circulating ROS directly damage the vascular endothelial surface, specifically its hyaluronan -rich protective glycocalyx, which depolymerises and thins, eventually exposing the plasma cell membrane to direct contact with activated leukocytes (156,157).…”

Section: Diabetic Retinopathy Is An Inflammatory Diseasementioning

confidence: 99%

“…All vessels are subject to the stress of blood flow and in capillaries the constant intimate contact with trafficking cells. Indeed the endothelial hyaluronan-rich glycocalyx appears designed to protect the endothelium from flow-cell damage (156,157). Endothelial cells therefore require a mechanism for repair/turnover which is provided by EPCs (169).…”

Section: Diabetic Retinopathy Is An Inflammatory Diseasementioning

confidence: 99%

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The Role of Inflammation in Diabetic Retinopathy

2020

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Inflammation is central to pathogenic processes in diabetes mellitus and the metabolic syndrome and particularly implicates innate immunity in the development of complications. Inflammation is a primary event in Type 1 diabetes where infectious (viral) and/or autoimmune processes initiate disease; in contrast, chronic inflammation is typical in Type 2 diabetes and is considered a sequel to increasing insulin resistance and disturbed glucose metabolism. Diabetic retinopathy (DR) is perceived as a vascular and neurodegenerative disease which occurs after some years of poorly controlled diabetes. However, many of the clinical features of DR are late events and reflect the nature of the retinal architecture and its cellular composition. Retinal microvascular disease is, in fact, an early event pathogenetically, induced by low grade, persistent leukocyte activation which causes repeated episodes of capillary occlusion and, progressive, attritional retinal ischemia. The later, overt clinical signs of DR are a consequence of the retinal ischemia. Metabolic dysregulation involving both lipid and glucose metabolism may lead to leukocyte activation. On a molecular level, we have shown that macrophage-restricted protein tyrosine phosphatase 1B (PTP1B) is a key regulator of inflammation in the metabolic syndrome involving insulin resistance and it is possible that PTP1B dysregulation may underlie retinal microvascular disease. We have also shown that adherent CCR5 + CD11b + monocyte macrophages appear to be selectively involved in retinal microvascular occlusion. In this review, we discuss the relationship between early leukocyte activation and the later features of DR, common pathogenetic processes between diabetic microvascular disease and other vascular retinopathies, the mechanisms whereby leukocyte activation is induced in hyperglycemia and dyslipidemia, the signaling mechanisms involved in diabetic microvascular disease, and possible interventions which may prevent these retinopathies. We also address a possible role for adaptive immunity in DR. Although significant improvements in treatment of DR have been made with intravitreal anti-VEGF therapy, a sizeable proportion of patients, particularly with sight-threatening macular edema, fail to respond. Alternative therapies targeting inflammatory processes may offer an advantage.

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Section: Diabetic Retinopathy Is An Inflammatory Diseasementioning

confidence: 99%

Section: Diabetic Retinopathy Is An Inflammatory Diseasementioning

confidence: 99%

The Role of Inflammation in Diabetic Retinopathy

2020

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“…HA plays a fundamental role in the maintenance of vascular integrity [20,25]. Removal of HA by hyaluronidase results in myocardial edema in perfused rat hearts [26].…”

Section: Discussionmentioning

confidence: 99%

“…Removal of endothelial HA with the HAS inhibitor 4-methylesculetin (4ME) greatly impaired the collateral artery remodeling process, in a femoral occlusion model, due to perturbed mechanotransduction and in turn lack of activation of the smooth muscle cells, necessary for vascular remodeling [19]. In particular, the critical involvement of HA microvascular complications such as in diabetes has been reviewed recently [20]. However, its role in microvascular perfusion and the process of angiogenesis is still not clear.…”

Section: Introductionmentioning

confidence: 99%

Loss of Endothelial Glycocalyx Hyaluronan Impairs Endothelial Stability and Adaptive Vascular Remodeling after Arterial Ischemia

Wang

Vries

Sol

et al. 2020

Cells

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We recently reported that loss of hyaluronan (HA) from the endothelial glycocalyx leads to loss of vessel stability in specific microcirculatory vascular beds. Here we hypothesized that such derangements in the glycocalyx may also impair the adaptive response to vascular ischemia. Endothelial specific conditional hyaluronan synthase 2-KO (Has2-cKO) mice revealed reduced endothelial HA expression and lower hindlimb perfusion at baseline compared to control mice. After a single ligation of the common femoral artery in these mice, we observed dysregulated angiogenesis in the gastrocnemius muscle which did not restore capillary perfusion. Mechanistically, decreased endothelial binding of the pericyte-derived molecule angiopoietin1 (Ang1) could be observed in the Has2-cKO mouse. In vitro angiogenesis assays with an endothelial cell-pericyte coculture confirmed such disturbed Ang1-TIE2 signaling resulting in excessive angiogenesis upon loss of HA. These data could be of relevance to diabetes patients, where we confirm loss of endothelial HA in the microcirculation of muscle tissue, indicating that this may contribute to the known disturbed adaptation to ischemia in these patients. In summary, loss of endothelial HA results in impaired microvascular perfusion and endothelial stability in ischemic gastrocnemius muscle. Endothelial HA is a potential target to improve angiogenic therapy in diabetic patients with critical limb ischemia.

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“…HS, on the other hand, was visualized as a shorter molecule with a straight positioning to the cell surface [37]. The HA network plays a major role in the stability and function of the EG, as passage through the EG is regulated by HA [126]. Moreover, endothelial mechanosensing and the preservation of endothelial quiescence are in need of the presence of HA [98].…”

Section: Endothelial Glycocalyxmentioning

confidence: 99%

Sirtuin 1 and endothelial glycocalyx

Lipphardt

Song

Goligorsky

2020

Pflugers Arch - Eur J Physiol

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Sirtuin1 deficiency or reduced activity comprises one of the hallmarks of diseases as diverse as chronic cardiovascular, renal, and metabolic, some malignancies, and infections, as well as aging-associated diseases. In a mouse model of endothelium-limited defect in sirtuin 1 deacetylase activity, we found a dramatic reduction in the volume of endothelial glycocalyx. This was associated with the surge in the levels of one of key scaffolding heparan sulfate proteoglycans of endothelial glycocalyx, syndecan-4, and specifically, its extracellular domain (ectodomain). We found that the defect in endothelial sirtuin 1 deacetylase activity is associated with (a) elevated basal and stimulated levels of superoxide generation (via the FoxO1 over-acetylation mechanism) and (b) increased nuclear translocation of NF-kB (via p65 over-acetylation mechanism). These findings laid the foundation for the proposed novel function of sirtuin 1, namely, the maintenance of endothelial glycocalyx, particularly manifest in conditions associated with sirtuin 1 depletion. In the forthcoming review, we summarize the emerging conceptual framework of the enhanced glycocalyx degradation in the states of defective endothelial sirtuin 1 function, thus explaining a broad footprint of the syndrome of endothelial dysfunction, from impaired flow-induced nitric oxide production, deterrent leukocytes infiltration, increased endothelial permeability, coagulation, and pro-inflammatory changes to development of microvascular rarefaction and progression of an underlying disease.

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Endothelial Glycocalyx Hyaluronan

Cited by 45 publications

References 89 publications

The Role of Inflammation in Diabetic Retinopathy

The Role of Inflammation in Diabetic Retinopathy

Loss of Endothelial Glycocalyx Hyaluronan Impairs Endothelial Stability and Adaptive Vascular Remodeling after Arterial Ischemia

Sirtuin 1 and endothelial glycocalyx

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