COVID-19 is normally associated with the lungs and respiratory system. Most people think of symptoms such as coughing and shortness of breath when they think of COVID-19. However, COVID-19 can impact the entire body and cause a wide range of symptoms and complications.
Strokes, a vascular system condition, are among the most common complications for people hospitalized with severe COVID-19. This led many researchers to question if COVID-19 is a vascular disease with respiratory symptoms.
Like so many things about COVID-19, we’re still not 100 percent certain of the answer to that question. However, the latest research shows that the vascular symptoms of COVID-19 are caused by inflammation and not COVID-19.
This means COVID-19 is still considered a respiratory disease, but it can have serious effects on the vascular system. Read on to learn more.
Medical professionals and researchers have been studying the link between COVID-19 and vascular symptoms since the beginning of the pandemic. They have learned that people with severe COVID-19 are at a risk of strokes, blood clots, and other vascular complications.
These observations led to several hypotheses that COVID-19 was a vascular disease with respiratory symptoms and not a respiratory disease.
Studies in 2020Trusted Source and 2021 supported this theory. These studies concluded that although people with mild to moderate COVID-19 only had respiratory symptoms, COVID-19 was primarily a vascular disease. However, additional studies published later in 2021Trusted Source and into 2022Trusted Source have contraindicated these findings. New studies indicate that COVID-19 doesn’t attack the vascular system at all.
Instead, these studies found that strokes and other vascular complications occur when infected respiratory cells cause extreme inflammation in other parts of your body.
Many people who are hospitalized for COVID-19 are at increased risk of vascular complications. Knowing that these complications are part of an inflammatory immune system response can help doctors lower the risk of stroke and other serious vascular complications.
For example, people with SARS-CoV-2 infections who are at risk of vascular complications may be given blood thinners to help lower their risk. Doctors, medical researchers, and other professionals might also look for ways to lower inflammation while still helping the body fight COVID-19.
Understanding how COVID-19 affects the vascular system can also help researchers identify people who are most at risk of vascular complications, leading to targeted treatments and better outcomes.
Like many things related to COVID-19, more research about this connection still needs to be done.
COVID-19 is known to have both short-term and long-term symptoms and complications. Some of these symptoms are respiratory and sensory. For instance, you might’ve read articles about people who lost their sense of smell for months following the development of COVID-19.
There are also long-term complications and symptoms associated with the vascular symptom. Not everyone will have these symptoms, but studying them has been an important part of researchers understanding how COVID-19 affects the vascular system.
Long-term vascular complications of COVID-19 include:
In studies, heart failure and arrhythmias were the most common vascular complications of COVID-19. However, the data on complications from COVID-19 is still very new.
People who have recovered from COVID-19 have only been observed for a year or two. What we know about vascular and other complications might change in the years to come as the first people who recovered from COVID-19 are observed for longer.
Additionally, new COVID-19 treatments might drastically change what complications look like for future SARS-CoV-2 infections.
Yes. COVID-19 can cause serious organ damage. Your lungs, liver, kidneys, brain, and heart can all be damaged by COVID-19.
Which organ is most often affected by COVID-19?
The lungs are the organs most affected by COVID-19. COVID-19 can irritate the lining of your lungs, cause inflammation in your lungs, cause your lungs to fill with fluid, and can cause damage to the lining of your lungs.
Not everyone who gets COVID-19 will experience lung damage. For many people, COVID-19 presents as a mild respiratory infection, but severe COVID-19 can lead to organ damage and even death.
Does COVID-19 damage your heart?
COVID-19 can cause damage to multiple organs, including damage to your heart. People who’ve recovered from severe COVID-19 are at an increased risk of heart complications. This indicates a strong link between COVID-19 and heart health.
Additionally, there’s evidence that people who already have heart conditions are at risk of more serious symptoms if they do develop COVID-19.
Since the early days of the pandemic, researchers have noticed that a large number of people hospitalized with severe COVID-19 had strokes, blood clots, and other vascular complications. This led to theories and studies about the link between COVID-19 and the vascular system.
Currently, researchers believe that the immune system attacks infected respiratory cells as they travel through the rest of the body. This response can sometimes cause significant inflammation, damage the lining of your blood vessels, and lead to blood clots.
More research still needs to be done on this topic, but what we now know is already helping doctors lower the risk of stroke and clots for those hospitalized with severe COVID-19.
In a retrospective study of 39 COVID-19 patients and 32 control participants in China, we collected clinical data and examined the expression of endothelial cell adhesion molecules by enzyme-linked immunosorbent assays. Serum levels of fractalkine, vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and vascular adhesion protein-1 (VAP-1) were elevated in patients with mild disease, dramatically elevated in severe cases, and decreased in the convalescence phase. We conclude the increased expression of endothelial cell adhesion molecules is related to COVID-19 disease severity and may contribute to coagulation dysfunction.Keywords: COVID-19, fractalkine, endothelial cell adhesion molecules, D-dimer, coagulopathy
In December 2019, a severe public health event, manifested mainly with fever and respiratory tract symptoms, broke out in Wuhan, China, and quickly spread throughout the country and the world , which was named coronavirus disease 2019 (COVID-19) by the World Health Organization. As of 1 May 2020, more than 3 million cases have been confirmed, while more than 200 000 patients have died, and the number is continuing to increase.
COVID-19 causes a systemic inflammatory response, involving dysregulation and misexpression of many inflammatory cytokines . The recruitment and activation of inflammatory cells depend on the expression of many classes of inflammatory mediators, such as cytokines (interleukin [IL]-1, IL-6, and IL-18), chemokines (fractalkine [FKN]), and adhesion molecules (intercellular adhesion molecule 1 [ICAM-1)] and vascular cell adhesion molecule-1 [VCAM-1]) . Pathological evidence of venous thromboembolism, direct viral infection of the endothelial cells, and diffuse endothelial inflammations have been reported in recent studies [2, 3]. Therefore, it is of significance to investigate the expression of endothelial cell adhesion molecules in COVID-19.
Here, we collected clinical data and blood samples from confirmed COVID-19 patients in the Fourth People’s Hospital of Yiyang in Hunan, China, and performed enzyme-linked immunosorbent assays (ELISAs) to study the expression of inflammatory mediators and endothelial cell adhesion molecules in COVID-19 patients.Go to:
A retrospective study was conducted. From 1 February to 10 March 2020, 39 COVID-19 patients were recruited at the Infectious Disease Ward in the Fourth People’s Hospital of Yiyang, Hunan, China, and 32 uninfected participants were recruited from the physical examination center of Hunan Provincial People’s Hospital. All patients tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and were hospitalized. Nine patients were diagnosed with severe pneumonia, while 30 had mild disease. Mild pneumonia was defined as positivity in quantitative reverse transcription polymerase chain reaction (qRT-PCR) tests, with typical chest tomography imaging features of viral pneumonia , while severe pneumonia was defined as mild pneumonia plus 1 of the following criteria: (1) respiratory distress with a respiratory rate ≥ 30 times per minute;
(2) oxygen saturation ≤ 93% at rest; (3) oxygenation index ≤ 300 mmHg (1 mmHg = 0.133 kPa); (4) respiratory failure requiring ventilation; (5) refractory shock; and
(6) admission to the intensive care unit for other organ failure. All patients were given interferon-α2b (5 million units twice daily, atomization inhalation) and lopinavir plus ritonavir (500 mg twice daily, orally) as antiviral therapy. All patients with severe disease received preventive anticoagulant treatment with low-molecular-weight heparin (LMWH) 5000 IU/day by subcutaneous injection for 7 days. No patients died during the observation period.
The criteria for discharge were: (1) absence of fever for at least 3 days; (2) significant improvement in both lungs on chest computed tomography (CT); (3) clinical remission of respiratory symptoms; and (4) repeated negativity in RT-PCR tests of throat swab samples at least 24 hours apart.
Clinical data were measured at enrolment. The study was approved by the Medical Ethics Review Board of Hunan Provincial People’s Hospital (No. 2020-10). All study participants provided written informed consent.
Blood samples were collected at admission from each patient in a fasting state and repeated during the convalescence period for severe cases. Serum lipids, glucose, C-reaction protein (CRP), and D-dimer were determined by conventional laboratory methods. Blood samples of control subjects were also collected and tested. The obtained blood samples were placed in tubes containing EDTA and immediately centrifuged at 1500g and stored at −80°C.
Enzyme-Linked Immunosorbent Assay
Quantitative determination of IL-18, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), FKN, VCAM-1, ICAM-1, and vascular adhesion protein-1 (VAP-1) was performed using commercially available ELISA kits (BOSTER).
Categorical variables were reported as number and percentages, and significance was detected by χ2 or Fisher exact test. The continuous variables were compared using independent group t tests and described using mean and standard deviation if normally distributed, or compared using the Mann-Whitney U test and Kruskal-Wallis H test and described using median and interquartile range (IQR) value if not. Paired comparisons of the severe group were analyzed with the Nemenyi test. Statistical analysis was performed by SPSS version 19.0. Two-sided P values < .05 were considered statistically significant.
Patient and Public Involvement
In this retrospective study, no patients were directly involved in the study design, question proposal, or the outcome measurements. No patients were asked for input concerning interpretation or recording of the results.
Demographic information is shown in Table 1. Briefly, 20 patients were male, 19 patients were female, 16 controls were male, and 16 were female, and the median ages in the control, mild, and severe groups were 52, 49, and 54 years, respectively. Nine patients had severe disease, while 30 cases had mild disease. No significant differences were found between patients with mild disease and control participants in age, smoking, cardiovascular disease (CVD), autoimmune disease, low-density lipoprotein cholesterol (LDL-C), triglycerides, total cholesterol (CHO), glucose, and D-dimer. Significant differences in D-dimer were observed between the severe disease and control participants (median, 4.49 vs 0.34, respectively; P < .05), while no significant differences in age, smoking, CVD, autoimmune disease, and the levels of triglycerides, LDL-C, CHO, and glucose were observed. Significant differences in age (median, 54 vs 49; P < .05), triglycerides (median, 0.93 vs 1.29; P < .05), D-dimer (median, 4.49 vs 0.35; P < .05), and length of stay (mean, 16.6 vs 10.6; P < .05) were observed between patients with severe and mild disease, respectively, while no significant differences in smoking, CVD, autoimmune disease, and the levels of LDL-C, CHO, and glucose were observed.
Characteristics of Study Participants
Sex, male/female, n/n
Age, y, median (25, 75 percentile)a
50 (42, 57)
52 (44, 60)
49 (25, 55)
54 (47, 75)*
Current smoker, n (%)
Cardiovascular disease, n (%)
Autoimmune disease, n (%)
LDL-C, mmol/L, median (25, 75 percentile)a
1.81 (1.53, 2.17)
1.81 (1.45, 2.03)
1.81 (1.52, 2.34)
2.11 (1.58, 2.41)
Triglycerides, mmol/L, median (25, 75 percentile)a
Expression of Inflammatory Mediators and Endothelial Cell Adhesion Molecules in COVID-19 Patients and Uninfected Participants
The serum levels of the following were higher in patients with mild disease than in control participants: FKN (median, 880.1 vs 684.6 pg/mL; P < .01); VCAM-1 (median, 3742.3 vs 891.4 pg/mL; P < .01); ICAM-1 (median, 2866.1 vs 1287.4 pg/mL; P < .01); VAP-1 (median, 16.81 vs 16.68 pg/mL; P = .41) (Figure 1A–D); CRP (median, 10.75 vs 1.59 mg/L; P < .01); IL-18 (median, 415.4 vs 276.5 pg/mL; P = .09); TNF-α (median, 257.1 vs 242.9 pg/mL; P < .01); and IFN-γ (median, 46.00 vs 42.51 pg/mL; P = .50) (Supplementary Figure 1A–D). Of these, CRP, TNF-α, FKN, VCAM-1, and ICAM-1 were significantly elevated.
Expression of endothelial cell adhesion molecules in COVID-19 patients and uninfected participants, the horizontal lines represent median with interquartile range: (A) fractalkine; (B) vascular cell adhesion molecule-1 (VCAM-1); (C) intercellular adhesion molecule 1 (ICAM-1); and (D) vascular adhesion protein-1 (VAP-1). * P < .05; ** P < .01.
The serum levels of the following were significantly higher in patients with severe disease than in control participants: FKN (median, 1457.5 vs 684.6 pg/mL; P < .01); VCAM-1 (median, 4991.3 vs 891.4 pg/mL; P < .01); ICAM-1 (median, 4498.2 vs 1287.4 pg/mL; P < .01); VAP-1 (median, 28.80 vs 16.68 pg/mL; P < .01) (Figure 1A–D); CRP (median, 43.64 vs 1.59 mg/L; P < .01); IL-18 (median, 670.7 vs 276.5 pg/mL; P < .01); TNF-α (median, 274.2 vs 242.9 pg/mL; P < .01); and IFN-γ (median, 76.50 vs 42.51 pg/mL; P < .01) (Supplementary Figure 1A–D).
The serum levels of the following were significantly higher in patients with severe disease than in patients with mild disease: FKN (median, 1457.5 vs 880.1 pg/mL; P < .01); VCAM-1 (median, 4991.3 vs 3742.3 pg/mL; P < .05); ICAM-1 (median, 4498.2 vs 2866.1 pg/mL; P < .05); VAP-1 (median, 28.80 vs 16.81 pg/mL; P < .01) (Figure 1A–D); CRP (median, 43.64 vs 10.75 mg/L; P < .01); IL-18 (median, 670.7 vs 415.4 pg/mL; P < .01); TNF-α (median, 274.2 vs 257.1 pg/mL; P < .05); and IFN-γ (median, 76.50 vs 46.00 pg/mL; P < .01) (Supplementary Figure 1A–D).
For severe cases, the serum levels of the following were lower in the convalescence phase than during the acute phase: FKN (median, 1028.2 vs 1457.5 pg/mL; P < .05); VCAM-1 (median, 3420.9 vs 4991.3 pg/mL; P < .01); ICAM-1 (median, 3046.9 vs 4498.2 pg/mL; P < .01); VAP-1 (median, 23.90 vs 28.80 pg/mL; P = .17) (Figure 1A–D); CRP (median, 10.20 vs 43.64 mg/L; P < .01); IL-18 (median, 514.6 vs 670.7 pg/mL; P < .01); TNF-α (median, 265.1 vs 274.2 pg/mL; P < .01); IFN-γ (median, 66.30 vs 76.50 pg/mL; P = .05) (Supplementary Figure 1A–D); and D-dimer (median, 0.45 vs 4.49; P < .01) (Supplementary Figure 2). Of these, IL-18, TNF-α, FKN, VCAM-1, ICAM-1, and D-dimer were significantly lower.Go to:
Three novel findings were identified in our study. First, the endothelial cell adhesion markers FKN, VCAM-1, and ICAM-1 were elevated in COVID-19 patients. Second, the severity of COVID-19 was associated with the serum levels of CRP, IL-18, TNF-α, IFN-γ, FKN, VCAM-1, ICAM-1, and VAP-1. Third, recovery from severe COVID-19 was associated with reductions in serum CRP, IL-18, TNF-α, FKN, VCAM-1, ICAM-1, and D-dimer levels.
Endothelial activation is related to severe COVID-19, and antiphospholipid antibodies, von Willebrand factor, and factor VIII may play a role in coagulopathy . Endothelial cells express angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2 , and the interaction of SARS-CoV-2 and ACE2 possibly mediates endothelial activation. Endothelial cells are an essential component of the coagulation system and their integrity and functionality are critical to maintaining hemostasis, whereas endothelial cell activation or injury may result in platelet activation, thrombosis, and inflammation . Dysfunctional endothelial cells activated by proinflammatory cytokines may contribute to the pathogenesis of thrombosis by altering the expression of pro- and antithrombotic factors [8, 9].
In this cohort of COVID-19 patients, although apparent thrombosis formation was excluded by Doppler ultrasound in deep veins in the lower extremities and repeated chest CT scans, we found an interesting phenomenon in patients with severe disease, that is serum D-dimer levels were elevated during the acute phase and decreased significantly during the convalescence phase. As an indirect marker of coagulation activation, elevated D-dimer has been reported in several studies and confirmed to correlate with an increased likelihood of death in COVID-19 patients . We consider that the relationship between prethrombosis levels of D-dimer and thrombotic disease is likely partly attributable to subclinical clot formation.
Severe COVID-19 is commonly complicated by coagulopathy, while disseminated intravascular coagulation may contribute to most deaths . Anticoagulant treatment may decrease mortality due to coagulopathy . In patients with severe disease, serum FKN, ICAM-1, VCAM-1, and D-dimer levels declined significantly after antiviral and anticoagulant treatment. In addition to stimulating the immune system to suppress viral replication and clear pathogens, interferon-α also inhibits the inflammatory immune response that leads to histological damage . Hence, we speculate that the dynamic changes in these molecules resulted from the alleviation of endothelial cell injuries, the anti-inflammatory effect of medications, or recovery from COVID-19.
Limitations should be noted when interpreting the results of this study. First, the number of patients with severe disease was low, which may lead to statistical deviation. Second, due to tissue sample inaccessibility, the expression of endothelial activation molecules was not measured in tissues. Third, because we did not measure the direct biomarkers in the coagulation system, the specific disturbed pathways and mechanisms are still unknown. Fourth, due to the anti-inflammatory effect of interferon-α, the relationship between the anticoagulant effect of LMWH and the decreased expression of endothelial cell adhesion molecules in COVID-19 is still uncertain, and requires further study.
In conclusion, based on the results of this study, increased expression of endothelial cell adhesion molecules is related to COVID-19 and disease severity, and may contribute to coagulation dysfunction.
Supplementary materials are available at The Journal of Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
Acknowledgments. We sincerely thank clinicians at the Forth People’s Hospital of Yiyang, Hunan, China.
Financial support. This work was supported by the Key Research and Development Program of Hunan Province (grant number 2020SK3011).
Potential conflicts of interest. All authors: No reported conflicts of interests. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.Go to:
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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause inflammatory lung disease, including clot formation and hyper-permeability of the lung vessels, resulting in edema and bleeding into the lung. Inflammation also affects other organs, mediated by the cytokine storm.
This inflammation is characterized by endothelial cell dysfunction in multiple organs. The cause of this endothelialopathy is unknown. It could be due to the direct infection of endothelial cells or an indirect effect of the cytokines.
Image Credit: Kateryna Kon/Shutterstock.com
Integrin binding by SARS-CoV-2
Unlike earlier coronaviruses pathogenic to humans, SARS-CoV-2 has a spike protein that is linked to host recognition and viral attachment via the angiotensin-converting enzyme 2 (ACE2) receptor. A unique three-residue RGD motif outside the ACE2 recognition site may allow the spike protein to bind to endothelial proteins called integrins, that bind the RGD group.
In fact, the major integrin on endothelial cells, called αVβ3, is able to bind to multiple RGD-binding ligands. It also engages multiple extracellular matrix proteins, such as fibrinogen, fibronectin, and vitronectin, via its binding pocket. These matrix proteins regulate cell adhesion, migration, and proliferation, as well as angiogenesis.
This mutation could thus enhance SARS-CoV-2 binding to the host cell and may be responsible for the high transmissibility of this virus compared to the earlier ones, while also allowing for multiple routes of entry for the virus and promoting its dissemination within the host by two receptors.
SARS-CoV-2 thus produces marked dysregulation of the endothelial barrier, causing it to lose its integrity and producing a hyper-permeable state. This leads to shock and the rapid spread of the virus to major organs.
Endothelial infection in COVID-19
Endothelial cells are key to several physiological processes including activation of immune cells, platelet aggregation and adhesion, leukocyte adhesion, and transmigration. They are also the target of many viruses, leading to multi-organ dysfunction.
Some studies have failed to show the growth of the virus within endothelial cells, which has been attributed to the lack of expression of the angiotensin-converting enzyme 2 (ACE2) receptor on these cells.
However, it may be argued that this is due to the intrinsic differences between the endothelial monolayer grown in vitro, vs the endothelial lining of the blood vessels that handle blood flowing under shear stress; the activation of the endothelial cells by the high volume of cytokines; and the tight contact with the epithelial cells of the lung capillaries.What is a Cytokine Storm?
Other researchers have reported that SARS-CoV-2 is found in association with the endothelial cell marker CD31 within the lungs, in infected mice and non-human primates (NHPs). Even more significantly, this finding has been identified in the lung tissue of people who died of severe COVID-19.
The viral proteins were also found in endothelial cells. Moreover, infected mice showed upregulated KRAS signaling pathways in lung tissue, known to mediate cellular activation and dysfunction. Experimental evidence shows that mouse endothelial cells are infected by SARS-CoV-2.
Though all endothelial cells express ACE2, all are not the targets of the virus. Instead, it requires the co-expression of other host proteases such as the transmembrane serine protease TMPRSS2, or cathepsins, that cleave the spike protein to its fusion conformation, allowing viral entry into the host cell via endocytosis.
Endothelial cell injury
Following the viral entry into the endothelial cell, it begins to translate its proteins, replicate itself, and may directly induce cell injury and apoptosis. Along with this, endothelial cells activate T cells, though less than other antigen-presenting cells do. In fact, endothelial cells activate only antigen-specific memory or effector T cells, not naïve lymphocytes.
In so doing, endothelial cells may promote the destruction of infected cells by presenting viral proteins to CD8 T cells. Moreover, endothelial cells in the microvasculature may cause memory or effector CD4 T cells to migrate through the endothelium. Antiviral cytokines including gamma-interferon (IFN-γ) may induce class I or II major histocompatibility complex (MHC) molecules, costimulatory molecules that are typically required for T cell activation to occur.
This means that the endothelial dysfunction caused by COVID-19 blocks lymphocyte activation via endothelial cells, causing an imbalance in the adaptive immune response.
The cytokine storm leads to a kind of overreach, causing further endothelial dysfunction. These cytokines include interleukin-6 (IL-6) that stimulates endothelial cell secretion of pro-inflammatory mediators and complement activation, thus further enhancing endothelial barrier breakdown.
Lymphocyte depletion often seen in COVID-19 could also be the result of the excessive inflammation induced by the endothelial cell injury. The reduced number of CD4 lymphocytes may cause an impaired response to the infection while also stimulating further inflammation. Thus, the hyper-inflammatory response in severe and critical COVID-19 could be due to endothelial cell infection and dysfunction.
Loss of endothelial barrier integrity
SARS-CoV-2 infection causes immune dysfunction as well as extensive endothelial injury, in addition to clotting defects and systemic microangiopathy. The poor disease outcome is mediated largely through the increased vascular permeability secondary to infection-related inflammation.
This hyper-permeability is associated with the leakage of both cellular and non-cellular components of the blood in the small blood vessels of the lung, causing the alveoli to become congested with liquid. The patient drowns in the fluid from the leaky blood vessels, which can endanger life by causing asphyxiation.
Simultaneously, the clotting cascades are dysregulated, causing microthrombi to form throughout the circulation, along with leukocyte infiltration. The endothelial cell dysfunction may cause further inflammation and leukocyte recruitment and adhesion.
Since endothelial cells express glycosaminoglycans and thrombomodulin on their cell surface, they inhibit the clotting cascade component, thrombin, as well as a protein inhibitor of tissue factor. Many relaxing factors such as nitric oxide (NO) and prostacyclin (PGI2) are also produced by these cells, thus blocking leukocyte and platelet adhesion and migration, smooth muscle proliferation, and exerting an anti-inflammatory, anti-apoptotic effect.
When the endothelial cells are injured by the viral invasion, they cease to exert their anticoagulant effect, leading to a thrombotic tendency that manifests as extensive microthrombi, hyaline membrane formation in the small arterioles of the lung, and diffuse alveolar injury.
Elevated D-dimer levels occur with this hypercoagulable state, causing poor outcomes and higher mortality with COVID-19. Multiple procoagulant mechanisms are at work, from the exposure of the tissue factor to clotting factors in the blood to the loss of endothelial integrity and thus activation of the intrinsic clotting pathway by the exposed matrix under the endothelial cell layer, to the devastating release of van Willebrand factor (vWF), due to endothelial dysfunction. This molecule acts to bridge platelets for aggregation and clot formation.
Infection of the endothelial cells could be associated with viral invasion of the adjacent tissues, that is, of the smooth muscle cells of the arteries and the cardiac myocytes.
Thus, SARS-CoV-2 infection of endothelial cells could be an underlying cause for the cardiovascular complications of COVID-19, including the end-stage multi-organ dysfunction. It is plausible that the endothelial cell apoptosis was seen in patients who have died of COVID-19, as well as the microthrombi scattered throughout the lung vascular bed along with right ventricular dysfunction, are associated with direct infection of the endothelial cells.
The binding of the spike protein to αVβ3 can be inhibited by the specific αVβ3-antagonist Cilengitide, an RGD tripeptide, that has a high affinity to this integrin and suppresses virus-endothelium binding at very low doses.
Other therapeutic strategies include serine protease inhibitors, renin-angiotensin-aldosterone system inhibitors, statins, heparin, corticosteroids, and IL-6 inhibitors, all of which act at least in part via stabilization and protection of endothelial integrity.
Salk researchers and collaborators show how the protein damages cells, confirming COVID-19 as a primarily vascular disease
April 30, 2021
LA JOLLA—Scientists have known for a while that SARS-CoV-2’s distinctive “spike” proteins help the virus infect its host by latching on to healthy cells. Now, a major new study shows that the virus spike proteins (which behave very differently than those safely encoded by vaccines) also play a key role in the disease itself.
The paper, published on April 30, 2021, in Circulation Research, also shows conclusively that COVID-19 is a vascular disease, demonstrating exactly how the SARS-CoV-2 virus damages and attacks the vascular system on a cellular level. The findings help explain COVID-19’s wide variety of seemingly unconnected complications, and could open the door for new research into more effective therapies.
“A lot of people think of it as a respiratory disease, but it’s really a vascular disease,” says Assistant Research Professor Uri Manor, who is co-senior author of the study. “That could explain why some people have strokes, and why some people have issues in other parts of the body. The commonality between them is that they all have vascular underpinnings.”
Salk researchers collaborated with scientists at the University of California San Diego on the paper, including co-first author Jiao Zhang and co-senior author John Shyy, among others.
While the findings themselves aren’t entirely a surprise, the paper provides clear confirmation and a detailed explanation of the mechanism through which the protein damages vascular cells for the first time. There’s been a growing consensus that SARS-CoV-2 affects the vascular system, but exactly how it did so was not understood. Similarly, scientists studying other coronaviruses have long suspected that the spike protein contributed to damaging vascular endothelial cells, but this is the first time the process has been documented.
In the new study, the researchers created a “pseudovirus” that was surrounded by SARS-CoV-2 classic crown of spike proteins, but did not contain any actual virus. Exposure to this pseudovirus resulted in damage to the lungs and arteries of an animal model—proving that the spike protein alone was enough to cause disease. Tissue samples showed inflammation in endothelial cells lining the pulmonary artery walls.
The team then replicated this process in the lab, exposing healthy endothelial cells (which line arteries) to the spike protein. They showed that the spike protein damaged the cells by binding ACE2. This binding disrupted ACE2’s molecular signaling to mitochondria (organelles that generate energy for cells), causing the mitochondria to become damaged and fragmented.
Previous studies have shown a similar effect when cells were exposed to the SARS-CoV-2 virus, but this is the first study to show that the damage occurs when cells are exposed to the spike protein on its own.
“If you remove the replicating capabilities of the virus, it still has a major damaging effect on the vascular cells, simply by virtue of its ability to bind to this ACE2 receptor, the S protein receptor, now famous thanks to COVID,” Manor explains. “Further studies with mutant spike proteins will also provide new insight towards the infectivity and severity of mutant SARS CoV-2 viruses.”
The researchers next hope to take a closer look at the mechanism by which the disrupted ACE2 protein damages mitochondria and causes them to change shape.
Other authors on the study are Yuyang Lei and Zu-Yi Yuan of Jiaotong University in Xi’an, China; Cara R. Schiavon, Leonardo Andrade, and Gerald S. Shadel of Salk; Ming He, Hui Shen, Yichi Zhang, Yoshitake Cho, Mark Hepokoski, Jason X.-J. Yuan, Atul Malhotra, Jin Zhang of the University of California San Diego; Lili Chen, Qian Yin, Ting Lei, Hongliang Wang and Shengpeng Wang of Xi’an Jiatong University Health Science Center in Xi’an, China.
The research was supported by the National Institutes of Health, the National Natural Science Foundation of China, the Shaanxi Natural Science Fund, the National Key Research and Development Program, the First Affiliated Hospital of Xi’an Jiaotong University; and Xi’an Jiaotong University.
In a year that has been filled with so many mysteries already, I have another very odd one to share with you. Emergency rooms are filled to overflowing all over America, and nobody can seem to explain why this is happening. Right now, the number of new COVID cases in the United States each day is less than half of what it was just a couple of months ago. That is really good news, and many believe that this is a sign that the pandemic is fading. Let us hope that is true. With less people catching the virus, you would think that would mean that our emergency rooms should be emptying out, but the opposite is actually happening. All across the country, emergency rooms are absolutely packed, and in many cases we are seeing seriously ill patients being cared for in the hallways because all of the ER rooms are already full.
Inside the emergency department at Sparrow Hospital in Lansing, Michigan, staff members are struggling to care for patients showing up much sicker than they’ve ever seen.
Tiffani Dusang, the ER’s nursing director, practically vibrates with pent-up anxiety, looking at patients lying on a long line of stretchers pushed up against the beige walls of the hospital hallways. “It’s hard to watch,” she said in a warm Texas twang.
But there’s nothing she can do. The ER’s 72 rooms are already filled.
Can anyone explain why this is happening?
If the number of COVID cases was starting to spike again, it would make sense for emergency rooms to be overflowing.
Months of treatment delays have exacerbated chronic conditions and worsened symptoms. Doctors and nurses say the severity of illness ranges widely and includes abdominal pain, respiratory problems, blood clots, heart conditions and suicide attempts, among other conditions.
That mention of “heart conditions” immediately got my attention, because I have been seeing this so much in the news recently.
Authors: Panagis Galiatsatos, M.D., M.H.S., Robert Brodsky, M.D.
COVID-19 is a very complex illness. The coronavirus that causes COVID-19 attacks the body in many different ways, ranging from mild to life threatening. Different organs and tissues of the body can be affected, including the blood.
Robert Brodsky, a blood specialist who directs the Division of Hematology, and Panagis Galiatsatos, a specialist in lung diseases and critical care medicine, talk about blood problems linked to SARS-CoV-2 — the coronavirus that causes COVID-19 — and what you should know.
Coronavirus Blood Clots
Blood clots can cause problems ranging from mild to life threatening. If a clot blocks blood flow in a vein or artery, the tissue normally nourished by that blood vessel can be deprived of oxygen, and cells in that area can die.
Some people infected with SARS-CoV-2 develop abnormal blood clotting. “In some people with COVID-19, we’re seeing a massive inflammatory response, the cytokine storm that raises clotting factors in the blood,” says Galiatsatos, who treats patients with COVID-19.
Brodsky notes that other serious illnesses, especially ones that cause inflammation, are associated with blood clots. Research is still exploring if the blood clots seen in severe cases of COVID-19 are unique in some way.
The Impact of Coronavirus Blood Clots Throughout the Body
In addition to the lungs, blood clots, including those associated with COVID-19, can also harm:
The nervous system. Blood clots in the arteries leading to the brain can cause a stroke. Some previously young, healthy people who have developed COVID-19 have suffered strokes, possibly due to abnormal blood clotting.
The kidneys. Clogging of blood vessels in the kidney with blood clots can lead to kidney failure. It can also complicate dialysis if the clots clog the filter of the machine designed to remove impurities in the blood.
Peripheral blood vessels and “COVID toe.” Small blood clots can become lodged in tiny blood vessels. When this happens close to the skin, it can result in a rash. Some people who test positive for COVID-19 develop tiny blood clots that cause reddish or purple areas on the toes, which can itch or be painful. Sometimes called COVID toe, the rash resembles frostbite.
Pulmonary thrombosis is observed in severe acute respiratory syndrome coronavirus 2 pneumonia. Aim was to investigate whether subpopulations of platelets were programmed to procoagulant and inflammatory activities in coronavirus disease 2019 (COVID-19) patients with pneumonia, without comorbidities predisposing to thromboembolism.
in a Coronavirus, that spike protein becomes part of the viral capsule. In other words, the cell wall around the virus, called the viral capsule. But it’s not in the virus. It’s in your cells. So it therefore becomes part of the cell wall of your vascular endothelium. Which means that these cells that line your blood vessels, which are supposed to be smooth so that blood flows smoothly, now have these little spikey bits sticking out.
So it is absolutely inevitable that blood clots will form. Because your blood platelets circulate around in your blood vessels. And the purpose of blood platelets is to detect a damaged vessel and block that vessel to stop bleeding. So when the platelet comes through the capillary, it suddenly hits all these all these Covid spikes that are jutting into the inside of the vessel, it is absolutely inevitable that a blood clot will form to block that vessel. That’s how platelets work.
SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection relies on the binding of S protein (Sprotein (Spike glycoprotein) to ACE (angiotensin-converting enzyme) 2 in the host cells. Vascular endothelium can be infected by SARS-CoV-2,1 which triggers mitochondrial reactive oxygen species production and glycolytic shift.2 Paradoxically, ACE2 is protective in the cardiovascular system, and SARS-CoV-1 S protein promotes lung injury by decreasing the level of ACE2 in the infected lungs.3 In the current study, we show that S protein alone can damage vascular endothelial cells (ECs) by downregulating ACE2 and consequently inhibiting mitochondrial function.
Whether it’s strange rashes on the toes or blood clots in the brain, the widespread ravages of COVID-19 have increasingly led researchers to focus on how the novel coronavirus sabotages blood vessels.
As scientists have come to know the disease better, they have homed in on the vascular system — the body’s network of arteries, veins and capillaries, stretching more than 60,000 miles — to understand this wide-ranging disease and to find treatments that can stymie its most pernicious effects.
Some of the earliest insights into how COVID-19 can act like a vascular disease came from studying the aftermath of the most serious infections. Those reveal that the virus warps a critical piece of our vascular infrastructure: the single layer of cells lining the inside of every blood vessel, known as the endothelial cells or simply the endothelium.