Vascular Endothelial Glycocalyx Damage in COVID-19

Abstract

The new coronavirus disease-2019 (COVID-19), which is spreading around the world and threatening people, is easily infecting a large number of people through airborne droplets; moreover, patients with hypertension, diabetes, obesity, and cardiovascular disease are more likely to experience severe conditions. Vascular endothelial dysfunction has been suggested as a common feature of high-risk patients prone to severe COVID-19, and measurement of vascular endothelial function may be recommended for predicting severe conditions in high-risk patients with COVID-19. However, fragmented vascular endothelial glycocalyx (VEGLX) is elevated in COVID-19 patients, suggesting that it may be useful as a prognostic indicator. Although the relationship between VEGLX and severe acute respiratory syndrome coronavirus 2 infections has not been well studied, some investigations into COVID-19 have clarified the relationship between VEGLX and the mechanism that leads to severe conditions. Clarifying the usefulness of VEGLX assessment as a predictive indicator of the development of severe complications is important as a strategy for confronting pandemics caused by new viruses with a high affinity for the vascular endothelium that may recur in the future.

Keywords: COVID-19; syndecan-1; systemic inflammatory-reactive microvascular endotheliopathy (SIRME); vascular endothelial dysfunction; vascular endothelial glycocalyx (VEGLX).

Figure 1

The number of global deaths due to the new coronavirus disease-2019 (COVID-19). The total number of global deaths due to COVID-19 was 1,372,182 as of 21 November 2020. The graph was generated from the COVID-19 Dashboard website by the Center for Systemics Science and Engineering at Johns Hopkins University (https://systems.jhu.edu. Last updated on 21 November 2020).

Figure 2

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) domain search. Results were obtained from the Basic Local Alignment Search Tool (BLAST) domain search of amino acid sequences translated from the genome sequence of the virus responsible for COVID-19 on 15 February 2020. The “Spike_rec_bind superfamily” domain, which is the 14th from the top, is called the spike receptor-binding super family and is described as binding to ACE2 angiotensin-converting enzyme 2 (ACE2). At that time, it was listed as “Wuhan seafood market pneumonia virus isolate Wuhan-Hu-1, complete genome” (https://www.ncbi.nlm.nih.gov/nuccore/NC_045512). As of 22 November 2020, it is listed as “Severe acute respiratory syndrome coronavirus 2 isolate Wuhan-Hu-1, complete genome”.

Figure 3

Renin-angiotensin system and angiotensin-converting enzyme 2 (ACE2). ACE2 was identified as an enzyme that degrades angiotensin II to angiotensin 1–7, which binds to the Mas receptor. The ACE2/angiotensin 1–7/Mas axis is an important repressor of the renin-angiotensin system. (↑) shows upregulation. AT1, angiotensin type 1 receptor; AT2, angiotensin type 2 receptor; Mas, G protein-coupled proto-oncogene Mas receptor; ROS, reactive oxygen species; NO, nitric oxide.

Figure 4

Severe COVID-19 comorbidity induced by vascular endothelial glycocalyx (VEGLX) damage. The VEGLX is damaged due to various factors such as smoking, physical inactivity, hypertension, diabetes, obesity, and cardiovascular diseases. Various lethal conditions in COVID-19 (e.g., acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), Kawasaki disease shock syndrome, microvascular thrombosis, etc.) may be caused by a common mechanism, damage of VEGLX. ROS, reactive oxygen species; RAAS, renin-angiotensin-aldosterone system; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease.

Figure 5

Vascular endothelial glycocalyx regulates cellular functions. Hyaluronic acid (HA) activates the HA/CD44 system by binding to CD44 and regulates various intracellular signaling through the multifunctional platform IQGAP1, as well as the vascular endothelial growth factor VEGF/VEGFR2 system. VEGF, vascular endothelial growth factor; VEGFR2, VEGF receptor 2; CD44, cluster of differentiation 44; CHD, calponin homology domain; IQ repeat, IQGAP specific repeat; ERK, extracellular-signal-regulated kinase; WW, region containing two tryptophans; S100B, S100 calcium-binding protein B; IQ motif, calmodulin-binding motif; Cdc42, cell division cycle 42; Rac1, Rac family small GTPase 1; GRD, Ras GTPase-activating protein-related domain; CLIP-170, cytoplasmic linker protein 170; RasGAP C, Ras GTPase-activating protein C terminus; ROS, reactive oxygen species.

Figure 6

Schematic representation of the vascular endothelial glycocalyx, which is present in the vascular endothelial cell membrane. The vascular endothelial glycocalyx is composed of core proteins and highly water-retaining glycosaminoglycans that bind to the cell membrane.

Figure 7

Intact vascular endothelial glycocalyx (VEGLX). When vascular endothelial cells are covered enough with healthy VEGLX, even if severe acute respiratory coronavirus 2 (SARS-CoV-2) enters the body, it could be neutralized by the effects of appropriate reactive oxygen species (ROS) and soluble angiotensin-converting enzyme 2 (sACE2), and it may be possible to prevent the virus entry into the vascular endothelium. VEGF, vascular endothelial growth factor; VEGFR, VEGF receptors; NO, nitric oxide; eNOS, endothelial NO synthase; TM, thrombomodulin; tPA, tissue plasminogen activator; PGI2, prostacyclin.

Figure 8

Damaged vascular endothelial glycocalyx (VEGLX). VEGLX damage is associated with vascular endothelial dysfunction, which induces reduced nitric oxide (NO) bioavailability, increased excessive reactive oxygen species (ROS) production, inflammatory cytokine release, platelet adherence, coagulation, and leukocyte adhesion. SARS-CoV-2, severe acute respiratory coronavirus 2; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor; ACE2, angiotensin-converting enzyme 2; sACE2, soluble ACE2; PAI-1, plasminogen activator inhibitor-1; TF, tissue factor; vWF, von Willebrand factor; ox-LDL, oxidized low-density lipoprotein; MMPs, matrix metalloproteases; tPA, tissue plasminogen activator; PGI2, prostacyclin; TM, thrombomodulin.

Figure 9

Conceptual diagram of the vascular endothelial glycocalyx (VEGLX) vulnerable region (PBR). The VEGLX, which covers the surface of vascular endothelial cells, can be broadly divided into a region of dense glycans on the vascular endothelial side and a region covered by fragile glycans on the vascular lumen side. In disorders of the VEGLX, the fragile region is known to be enlarged.

Figure 10

Conceptual diagram showing the relationship between shock-induced endotheliopathy (SHINE)/systemic inflammatory-reactive syndrome (SIRS) and the vascular endothelial glycocalyx (VEGLX) damage that causes systemic inflammation-reactive microvascular endotheliopathy (SIRME). SIRME is caused by a systemic disorder of the VEGLX, resulting in extravascular leakage of plasma components, increased thrombogenicity, increased production of reactive oxygen species, and an excess state of inflammatory cytokines, leading to microvascular embolism, venous thrombosis, and Kawasaki disease shock syndrome. As the disease worsens, it progresses to severe SIRME, including the concept of SIRS and SHINE, leading to severe conditions such as disseminated intravascular coagulation (DIC) and acute respiratory distress syndrome (ARDS).

Figure 11

Definition of systemic inflammatory-reactive microvascular endotheliopathy (SIRME). SIRME is caused by damage to the vascular endothelial glycocalyx (VEGLX), which is impaired in an inflammatory response. SIRME is characterized by (1) the presence of causative strong inflammation, (2) vascular endothelial damage with strong thrombogenic tendency and increased vascular permeability, (3) organ failure. SIRME is presumed to be one of the major mechanisms causing diverse complications of COVID-19. (↑) shows upregulation. VE, vascular endothelial; VEGLX, vascular endothelial glycocalyx; TIA, transient ischemic attack; ACS, acute coronary syndrome; ARDS, acute respiratory distress syndrome; DVT, deep vein thrombosis; DIC: disseminated intravascular coagulation; SIRS, systemic inflammatory response syndrome.

Figure 12

Chest radiograph of a patient with mild COVID-19. The fever of 38 °C lasted only half a day, and the next day, cough and nasal discharge were noted. A polymerase chain reaction (PCR) test for SARS-CoV-2 in a nasopharyngeal swab was performed 2 days after the fever was positive, and the patient was admitted to our hospital 2 days later. On admission, the patient had a low-grade fever, cough, nasal discharge, and conjunctival hyperemia, and chest radiographs showed multiple faint frosted shadows in the bilateral lung fields (left). With follow-up observation alone, the patient’s common cold-like symptoms were mild, and the abnormal shadows on the lungs had nearly disappeared by the ninth day of the disease (right). The patient was then discharged after two PCR tests confirmed negative results.

Figure 13

Chest computed tomography (CT) of a patient with mild COVID-19, the same patient as in Figure 12. On the second day, there were multiple faint frosted shadows bilaterally (left), but by the tenth day, the abnormal shadows had almost disappeared (right).

Figure 14

A flowchart depicting the selection process. A total of 16 studies were imported for title and abstract screening after removing duplicates, and 2 studies were retained. After a total of 11 studies were deemed eligible for full-text review, 6 reports [3,87,88,89,90,91] were included in Table 3.