☆ 4.7 Article

COVID-19 generates hyaluronan fragments that directly induce endothelial barrier dysfunction

JCI INSIGHT (2021)

Journal

JCI INSIGHT

Volume 6, Issue 17, Pages -

Publisher

AMER SOC CLINICAL INVESTIGATION INC

DOI: 10.1172/jci.insight.147472

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Funding

NIH grant: National Heart, Lung, and Blood Institute [R00HL135265, R01HL130541, R01HL142804]
NIH grant: National Institute on Aging [K01AG059892, R01AG048022, R56AG059877]
NIH grant: National Institute of Neurological Disorders and Stroke grant [U24NS107228]
University of Utah
United States Department of Veterans Affairs Clinical Sciences R&D (CSRD) Service [I01 CX001696]

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Abstract

Vascular injury in COVID-19 patients is linked to increased levels of glycosaminoglycans, particularly hyaluronan fragments and hyaluronidase activity. This damage to the glycocalyx is associated with disease severity and elevated levels of inflammatory cytokines. Pulmonary microvascular endothelial cells exposed to the COVID-19 milieu exhibit dysregulated HA biosynthesis and degradation, leading to the release of pathological HA fragments into circulation.

Vascular injury has emerged as a complication contributing to morbidity in coronavirus disease 2019 (COVID-19). The glycosaminoglycan hyaluronan (HA) is a major component of the glycocalyx, a protective layer of glycoconjugates that lines the vascular lumen and regulates key endothelial cell functions. During critical illness, as in the case of sepsis, enzymes degrade the glycocalyx, releasing fragments with pathologic activities into circulation and thereby exacerbating disease. Here, we analyzed levels of circulating glycosaminoglycans in 46 patients with COVID-19 ranging from moderate to severe clinical severity and measured activities of corresponding degradative enzymes. This report provides evidence that the glycocalyx becomes significantly damaged in patients with COVID-19 and corresponds with severity of disease. Circulating HA fragments and hyaluronidase, 2 signatures of glycocalyx injury, strongly associate with sequential organ failure assessment scores and with increased inflammatory cytokine levels in patients with COVID-19. Pulmonary microvascular endothelial cells exposed to COVID-19 milieu show dysregulated HA biosynthesis and degradation, leading to production of pathological HA fragments that are released into circulation. Finally, we show that HA fragments present at high levels in COVID-19 patient plasma can directly induce endothelial barrier dysfunction in a ROCK-and CD44-dependent manner, indicating a role for HA in the vascular pathology of COVID-19.

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Sex-Dependent Impairment of Endothelium-Dependent Relaxation in Aorta of Mice with Overexpression of Hyaluronan in Tunica Media

Karen Axelgaard Lorentzen, Raquel Hernanz, Estefano Pinilla, Jens Randel Nyengaard, Lise Wogensen, Ulf Simonsen

Summary: Diabetic macroangiopathy is characterized by extracellular matrix deposition, vessel thickening, and endothelial dysfunction. The overexpression of hyaluronan in the tunica media was found to induce endothelial dysfunction, oxidative stress, and increased EC-EC distances in the aortas of male mice. These findings suggest a sex-specific decrease in NO levels and impaired endothelial function in male mice with excessive hyaluronan accumulation.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2023)