Circulating Heparan Sulfate Proteoglycans as Biomarkers in Health and Disease

Lepedda, Antonio Junior; Nieddu, G.; Piperigkou, Zoi; Kyriakopoulou, Konstantina; Karamanos, Nikos K.; Formato, Marilena

doi:10.1055/s-0041-1725063

Cited by 29 publications

(30 citation statements)

References 141 publications

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“…These molecules participate in a number of vascular events such as regulation of vascular permeability, lipid metabolism, hemostasis, and thrombosis, as well as interact with vascular cells, growth factors, and cytokines, in order to modify vascular cell adhesion, migration, and proliferation. Some PGs exert specific functions in their soluble forms following cleavage by proteolytic enzymes ( Lepedda et al, 2021 ). The amount of PGs in the artery wall is physiologically low, but increases deeply during the early phases of atherosclerotic lesion formation.…”

Section: Significance Of Proteoglycans and Glycosaminoglycans In Vascular Biologymentioning

confidence: 99%

Glycosaminoglycans: From Vascular Physiology to Tissue Engineering Applications

et al. 2021

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Cardiovascular diseases represent the number one cause of death globally, with atherosclerosis a major contributor. Despite the clinical need for functional arterial substitutes, success has been limited to arterial replacements of large-caliber vessels (diameter > 6 mm), leaving the bulk of demand unmet. In this respect, one of the most challenging goals in tissue engineering is to design a “bioactive” resorbable scaffold, analogous to the natural extracellular matrix (ECM), able to guide the process of vascular tissue regeneration. Besides adequate mechanical properties to sustain the hemodynamic flow forces, scaffold’s properties should include biocompatibility, controlled biodegradability with non-toxic products, low inflammatory/thrombotic potential, porosity, and a specific combination of molecular signals allowing vascular cells to attach, proliferate and synthesize their own ECM. Different fabrication methods, such as phase separation, self-assembly and electrospinning are currently used to obtain nanofibrous scaffolds with a well-organized architecture and mechanical properties suitable for vascular tissue regeneration. However, several studies have shown that naked scaffolds, although fabricated with biocompatible polymers, represent a poor substrate to be populated by vascular cells. In this respect, surface functionalization with bioactive natural molecules, such as collagen, elastin, fibrinogen, silk fibroin, alginate, chitosan, dextran, glycosaminoglycans (GAGs), and growth factors has proven to be effective. GAGs are complex anionic unbranched heteropolysaccharides that represent major structural and functional ECM components of connective tissues. GAGs are very heterogeneous in terms of type of repeating disaccharide unit, relative molecular mass, charge density, degree and pattern of sulfation, degree of epimerization and physicochemical properties. These molecules participate in a number of vascular events such as the regulation of vascular permeability, lipid metabolism, hemostasis, and thrombosis, but also interact with vascular cells, growth factors, and cytokines to modulate cell adhesion, migration, and proliferation. The primary goal of this review is to perform a critical analysis of the last twenty-years of literature in which GAGs have been used as molecular cues, able to guide the processes leading to correct endothelialization and neo-artery formation, as well as to provide readers with an overall picture of their potential as functional molecules for small-diameter vascular regeneration.

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Section: Significance Of Proteoglycans and Glycosaminoglycans In Vascular Biologymentioning

confidence: 99%

Glycosaminoglycans: From Vascular Physiology to Tissue Engineering Applications

et al. 2021

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“…In patients with preeclampsia, placenta-derived, circulating soluble VEGF receptor and soluble endoglin inhibit VEGF-and BMP-9 signaling pathways leading to glomerular EC de-differentiation (3,287,288). Along with the ultrastructural EC changes, reduced EC glycocalyx/ESL height and shedding of glycocalyx components into the circulation have been documented in preeclampsia (171,174,202,289). The use of VEGF inhibitors to reduce tumor angiogenesis (290) and macular degeneration (5) can evoke a similar syndrome of albuminuria, sometimes in the nephrotic range, and hypertension.…”

Section: Albuminuria Reflects Glomerular Endothelial Barrier Dysfunction In Preeclampsiamentioning

confidence: 99%

“…Protease-dependent syndecan shedding ( 126 , 127 , 160 , 172 , 173 ) produces bioactive soluble syndecan fragments generally inhibiting the inflammatory response ( 160 ). Syndecan shedding is now widely recognized as a biomarker of EC glycocalyx disruption ( 174 ) and is associated with a reduced glycocalyx thickness and a reduced barrier function resulting in edema formation and albuminuria ( 175 ). While cleavage of HS and CS GAGs reduces the size and barrier of the glycocalyx in glomerular and non-glomerular EC, endothelial-specific deletion of syndecan 1 alone only reduced the height of the glycocalyx but did not change its barrier function ( 176 ).…”

Section: Molecular Components Of the Ec Glycocalyxmentioning

confidence: 99%

The Glomerular Endothelium Restricts Albumin Filtration

2021

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Inflammatory activation and/or dysfunction of the glomerular endothelium triggers proteinuria in many systemic and localized vascular disorders. Among them are the thrombotic microangiopathies, many forms of glomerulonephritis, and acute inflammatory episodes like sepsis and COVID-19 illness. Another example is the chronic endothelial dysfunction that develops in cardiovascular disease and in metabolic disorders like diabetes. While the glomerular endothelium is a porous sieve that filters prodigious amounts of water and small solutes, it also bars the bulk of albumin and large plasma proteins from passing into the glomerular filtrate. This endothelial barrier function is ascribed predominantly to the endothelial glycocalyx with its endothelial surface layer, that together form a relatively thick, mucinous coat composed of glycosaminoglycans, proteoglycans, glycolipids, sialomucins and other glycoproteins, as well as secreted and circulating proteins. The glycocalyx/endothelial surface layer not only covers the glomerular endothelium; it extends into the endothelial fenestrae. Some glycocalyx components span or are attached to the apical endothelial cell plasma membrane and form the formal glycocalyx. Other components, including small proteoglycans and circulating proteins like albumin and orosomucoid, form the endothelial surface layer and are bound to the glycocalyx due to weak intermolecular interactions. Indeed, bound plasma albumin is a major constituent of the endothelial surface layer and contributes to its barrier function. A role for glomerular endothelial cells in the barrier of the glomerular capillary wall to protein filtration has been demonstrated by many elegant studies. However, it can only be fully understood in the context of other components, including the glomerular basement membrane, the podocytes and reabsorption of proteins by tubule epithelial cells. Discovery of the precise mechanisms that lead to glycocalyx/endothelial surface layer disruption within glomerular capillaries will hopefully lead to pharmacological interventions that specifically target this important structure.

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“…Lepedda et al then introduce the diagnostic and prognostic value of circulating HSPGs. 7 The level of HSPG released into the bloodstream is demonstrated to correlate with disease severity in various pathologies such as cardiovascular disease, cancer, sepsis, and trauma. Whether the level of HSPG shed into plasma could be used as a prognostic biomarker in health and disease needs to be further investigated.…”

Section: Hspgs As Biomarkers and Treatment Targetsmentioning

confidence: 99%