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

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.

Automated summary

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.