Hyaluronan and Its Receptors as Regulatory Molecules of the Endothelial Interface

Queisser, Kimberly; Mellema, Rebecca A.; Petrey, Aaron C.

doi:10.1369/0022155420954296

Cited by 30 publications

(23 citation statements)

References 90 publications

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“…Of particular significance, a substantial portion of this HA occupied the central lumen rather than being restricted only to the luminal surface of the ECs in a classical vascular glycocalyx. 37,38 In contrast to the presence of HA in HUVEC tube lumens, we did not detect HA on the exterior of HUVEC tubes, which may reflect the reported absence of an abluminal polysaccharide layer near the growing tips of neovessels in vivo. 37 The absence of abluminal HA on our HUVEC tubes does not, by itself, indicate a complete absence of an exterior cell coat, as we have previously shown that biglycan is present on the exterior surfaces of these tubes.…”

Section: Discussioncontrasting

confidence: 59%

“…At present, the means by which endogenous HA could contribute to lumen development is not clear. Purified o-HA is reported to stimulate EC proliferation, migration, secretion of angiogenic factors, and overall vascular growth via receptor-mediated (e.g., CD44/ RHAMM) signaling, 38,44 although the direct involvement of o-HA in lumen development has not been established. Of note, there are concerns that some of the biological effects of LMW-HA/o-HA (e.g., induction of inflammatory responses) may be the consequence of contamination with endotoxin, 14 which has been shown to elicit proangiogenic behaviors in ECs.…”

Section: Discussionmentioning

confidence: 99%

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Autocrine Hyaluronan Influences Sprouting and Lumen Formation During HUVEC Tubulogenesis In Vitro

Vernon

Gooden

Chan

et al. 2021

J Histochem Cytochem.

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Although many studies have focused on a role for hyaluronan (HA) of interstitial extracellular matrix (presumably produced by non-vascular “stromal” cells) in regulating vascular growth, we herein examine the influence of “autocrine HA” produced by vascular endothelial cells themselves on tubulogenesis, using human umbilical vein endothelial cells (HUVECs) in angiogenic and vasculogenic three-dimensional collagen gel cultures. Relative to unstimulated controls, tubulogenic HUVECs upregulated HAS2 mRNA and increased the synthesis of cell-associated HA (but not HA secreted into media). Confocal microscopy/immunofluorescence on cultures fixed with neutral-buffered 10% formalin (NBF) revealed cytoplasmic HAS2 in HUVEC cords and tubes. Cultures fixed with NBF (with cetylpyridinium chloride added to retain HA), stained for HA using “affinity fluorescence” (biotinylated HA-binding protein with streptavidin-fluor), and viewed by confocal microscopy showed HA throughout tube lumens, but little/no HA on the abluminal sides of the tubes or in the surrounding collagen gel. Lumen formation in angiogenic and vasculogenic cultures was strongly suppressed by metabolic inhibitors of HA synthesis (mannose and 4-methylumbelliferone). Hyaluronidase strongly inhibited lumen formation in angiogenic cultures, but not in vasculogenic cultures (where developing lumens are not open to culture medium). Collectively, our results point to a role for autocrine, luminal HA in microvascular sprouting and lumen development. (J Histochem Cytochem 69: 415–428, 2021)

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Section: Discussioncontrasting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Autocrine Hyaluronan Influences Sprouting and Lumen Formation During HUVEC Tubulogenesis In Vitro

Vernon

Gooden

Chan

et al. 2021

J Histochem Cytochem.

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“…The rate of HA synthesis depends on the availability of substrate sugars (129), and conversely, high rates of HA synthesis are associated with a shift of cellular metabolism to glycolysis (130)(131)(132). HA binds to cell-surface receptors CD44 (133), RHAMM (receptor hyaluronan mediated motility) (134) and the lymphatic EC receptor LYVE-1. The cytoplasmic domain of CD44, a single pass membrane-spanning receptor, is coupled to cortical actin by ERM (ezrin radixin moesin) proteins (135).…”

Section: Hyaluronic Acid/hyaluronanmentioning

confidence: 99%

“…HA polymers are hydrated with 15 H 2 O molecules per disaccharide unit ( 145 ). At the apical/luminal EC surface HA interweaves with other components of the glycocalyx/ESL ( 110 , 134 ) and shear stress ( 129 , 146 ) and inflammatory stimuli ( 147 ) augment HA accumulation in the EC glycocalyx. HA binds proteoglycans in the hyalectin family (see below) forming large, patterned aggregates.…”

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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“…Moving from metabolic regulation of HA on to the function of HA and its receptor, CD44, Queisser, Mellema, and Petrey introduce us to the glycocalyx. 9 This specialized extracellular matrix, rich in HA and other GAGs, is located between blood and the endothelial surface and has critical roles in homeostatic vascular function. In contrast to the role of metabolic flux in regulating HAS activity discussed above, here the authors introduce the role that HA and the proteins to which it binds plays as mechanosensory transducers, transmitting extracellular signals into the cell.…”

mentioning

confidence: 99%

Exciting New Developments and Emerging Themes in Glycosaminoglycan Research

Merry

2020

J Histochem Cytochem.

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In times where many people have suffered loss and others of us are dealing with stress, disruption, and fear, there is a lot of comfort to be taken in reading. If we are not able to meet up and discuss our work in person, exploring published studies provides some succor, even without the cheese, wine, and other traditions of our usual get-togethers. Fortunately, recent months have seen many high-quality papers around the topic of glycosaminoglycans. I can only pick up on a very few here, those that I have particularly enjoyed, but the following collection of reviews will also be a treat and hopefully tide us over until our research community can regroup:

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Hyaluronan and Its Receptors as Regulatory Molecules of the Endothelial Interface

Cited by 30 publications

References 90 publications

Autocrine Hyaluronan Influences Sprouting and Lumen Formation During HUVEC Tubulogenesis In Vitro

Autocrine Hyaluronan Influences Sprouting and Lumen Formation During HUVEC Tubulogenesis In Vitro

The Glomerular Endothelium Restricts Albumin Filtration

Exciting New Developments and Emerging Themes in Glycosaminoglycan Research

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