Insights into Endotheliopathy in COVID-19

Abstract

Severe COVID-19 is characterized by a disruption of barrier function between the pulmonary circulation and alveoli, leading to characteristic alveolar infiltrates, hypoxemia, and in the worst case acute respiratory distress syndrome (ARDS) (1). Endothelial integrity plays an important role in maintaining the pulmonary capillary-alveolar barrier. Autopsy studies have shown that severe COVID-19 is associated with endothelial cell damage, perivascular inflammatory cell infiltration, with interstitial edema and alveolar space fluid consolidation (2). Clinical studies measuring circulating endothelial biomarkers support the hypothesis that endothelial dysfunction is an underlying factor in COVID-19 pathogenesis and a harbinger of poor outcome (3). Despite evidence that lung endothelial injury plays a key role in severe COVID-19, there has been relatively little translational investigation focusing on pulmonary vascular endothelium and its response to SARS-CoV-2 infection. Joffre et al., here, employed an ex vivo model of non-COVID-19 cadaveric primary human lung microvascular endothelial cells (HMVECs) from 6 non-COVID-19 donors to systematically study endothelial responses to live SARS-CoV-2 virus, inactivated virus, spike protein, and sera from acutely-ill COVID-19 patients (4). Authors demonstrated that live SARS-CoV-2 virus exposed to HMVECs directly infects and replicates within endothelial cells. This is consistent with a prior study of viral infection introduced in bioengineered human sinusoidal cells (5), and autopsy studies that have shown intracellular virus within capillary endothelium (2), Joffre's findings support a hypothesis that pulmonary capillary endothelia provide an environment for viral replication, facilitating viral access to the systemic circulation.Authors further demonstrated that SARS-CoV-2 infected HMVECs exhibit increased endothelial permeability as inferred using transepithelial resistance (TER). The increase in permeability was particularly sizable in 3 of the 6 HMVEC donors, although significant in all. Thus, direct pulmonary endothelial cell infection contributes to increased endothelial barrier permeability and may play a role in exacerbating pulmonary interstitial edema and transmigration of inflammatory

COVID-19 and abnormal uterine bleeding: potential associations and mechanisms

“…COVID-19-related endothelial dysfunction in the form of aberrant vascular tone, excessive inflammation, cytokine storm, oxidative stress, endothelial mesenchymal transition, mitochondrial dysfunction, virus-induced senescence and coagulopathy has been reported [ 97 , 98 ]. As well as the endothelial dysfunction associated with acute lung injury [ 99 ], COVID-19 has been shown to be a risk factor for more systemic endothelial dysfunction, for example, increasing the risk of myocardial infarction and ischaemic stroke [ 100 ]. The evidence for end organ endothelial cell dysfunction resulting in pathology raises the possibility that endometrial vascular function could be perturbed following SARS-CoV-2 infection, either directly or indirectly, resulting in menstrual disturbance.…”

Reduction in D-dimer Levels After Treatment with Auxora in Patients with Severe Covid-19 Pneumonia Reflects Endothelial Stabilization

“…5 Dexamethasone was noted in a pilot study of 31 patients with severe COVID-19 to reduce markers of endothelial activation 6 suggesting that the mechanism for the bene cial effect of dexamethasone may be multifactorial and potentially include endothelial stabilizing properties mediated via endothelial glucocorticoid receptors in addition to its anti-in ammatory effects. 7 This has not been evaluated in larger studies. Tocilizumab, a recombinant humanized monoclonal antibody against the interleukin-6 (IL-6) receptor, was noted in a trial of 80 patients with rheumatoid arthritis to improve endothelial function through a reduction in the in ammatory burden.…”

Reduction in D-dimer Levels After Treatment with Auxora in Patients with Severe Covid-19 Pneumonia Reflects Endothelial Stabilization

“…Dexamethasone remains the cornerstone of therapy for hospitalized patients with COVID-19 pneumonia needing oxygen therapy, while tocilizumab and baricitinib are recommended additions for those with a greater severity of illness [5]. Dexamethasone was noted in a pilot study of 31 patients with severe COVID-19 to reduce markers of endothelial activation [6] suggesting that the mechanism for the bene cial effect of dexamethasone may be multifactorial and potentially include endothelial stabilizing properties mediated via endothelial glucocorticoid receptors in addition to its anti-in ammatory effects [7]. This has not been evaluated in larger studies.…”