Investigation of SARS-CoV-2-related endothelial dysfunction

A recent study published in Acta Pharmacologica Sinica We described the evidence, mechanisms, and treatments for endothelial dysfunction in coronavirus disease 2019 (COVID-19).

COVID-19 has become a major public health emergency worldwide. Both the pulmonary and extrapulmonary systems are targeted by the causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The vascular endothelium provides a dynamic interface between blood and tissues/organs and maintains tissue homeostasis.

A large number of viruses can infect the endothelium and cause endothelial dysfunction. Accumulating evidence suggests that endothelial dysfunction is a key mechanism in the pathogenesis of her COVID-19. In this study, the investigator reviewed the contribution and tools of endothelial dysfunction in his COVID-19 and its complications and biomarkers.

Endothelial function and dysfunction

Endothelial functions include barrier integrity, anti-inflammatory, antioxidant, maintenance of the thrombotic interface, regulation of homeostasis, vascular tone, and cellular metabolism of amino acids, glucose. etcThe endothelium is responsible for vasoconstrictor and vasodilatory responses, prothrombolytic and antithrombotic responses, fibrinolytic and antifibrinolytic responses, prooxidant and antioxidant responses, and proinflammatory and antiinflammatory responses. It produces multiple vasoactive molecules that tightly regulate the balance between anti-inflammatory responses.

Nitric oxide (NO), produced by endothelial NO synthase (eNOS), is critical for endothelial homeostasis. Endothelial dysfunction is characterized by decreased bioavailability of NO and elevated levels of angiotensin II (Ang II), endothelin-1, and others. ROS inactivate eNOS and cause eNOS detachment.

Endothelial dysfunction in COVID-19

SARS-CoV-2 can cause systemic vascular injury through angiotensin-converting enzyme 2 (ACE2) binding. ACE2 is the receptor used by SARS-CoV-2 to enter host cells, including endothelial cells. Analysis of autopsy tissue from COVID-19 patients showed high ACE2 expression in capillaries but low in venules and arterioles compared to SARS-CoV-2-naive subjects .

There is no detectable ACE2 expression in major coronary arteries, suggesting that SARS-CoV-2-induced endotheliitis occurs in small capillaries. Lung endothelial cells have minimal ACE2 expression under normal conditions, but heterogeneous ACE2 levels and endothelial damage have been documented in autopsy tissue from COVID-19 patients.

Several histopathological analyzes have provided evidence for direct infection of endothelial cells by SARS-CoV-2. Electron microscopy (EM) examination of kidney tissue showed evidence of endothelial inflammation and viral particles in endothelial cells.

Mechanisms and markers of endothelial dysfunction in COVID-19

COVID-19 can have serious consequences cytokine storm Caused by overproduction of inflammatory mediators in a subset of critically ill patients. A study found markers associated with endothelial inflammation in lung tissue from COVID-19 patients. Moreover, in her severe COVID-19 case, exosomes activated caspase-1 and NLR-family pyrin domain-containing 3 (NLRP3) inflammasomes to release interleukin (IL)-1-beta in endothelial cells. has been proven.

Moreover, SARS-CoV-2 infection of brain microvascular endothelial cells showed increased endothelial cell apoptosis. RNA sequencing (RNA-seq) data showed upregulation of markers associated with endothelial activation. Therefore, SARS-CoV-2-associated inflammasome activation and hyperinflammation may lead to endothelial cell damage and death.

In particular, cytokine storm can cause vascular leakage, especially endothelial permeability. These cytokines disrupt the integrity of junctional proteins and can lead to extravasation of immune and inflammatory cells. One study noted a significant increase in angiogenesis in lung tissue from COVID-19 patients.

Furthermore, plasma profiling shows increased circulating levels of angiogenic markers. vascular endothelial growth factor A (VEGF-A), COVID-19 patient. Elevated VEGF-A levels promote inflammatory cell infiltration and endothelial leakage.

Multiple studies have reported elevated secretion of various markers of endothelial activation or dysfunction in COVID-19 patients. These include D-dimer, von Willebrand factor (vWF), factor VIII, soluble intercellular adhesion molecule 1 (sICAM1), soluble thrombomodulin (sTM), angiopoietin-2, VEGF-A, IL-6, IL- 8, lactic acid, and syndecan-1, etc.

Therapeutic agents for endothelial dysfunction

Statins exhibit lipid-lowering, anti-inflammatory, oxidative, thrombotic, and immunomodulatory effects. Therefore, they can be used as adjunctive therapy for SARS-CoV-2-associated endothelial dysfunction. The pharmacological profile of metformin, a first-line treatment for type 2 diabetes, makes it a promising candidate for repurposing to control inflammation in her COVID-19 patients with diabetes.

Several clinical trials suggest that the glucocorticoid dexamethasone may benefit COVID-19 patients. Dexamethasone treatment in her severe COVID-19 patient significantly reduced the levels of endothelial dysfunction-related markers. Tocilizumab, a humanized monoclonal antibody, reduces oxidative stress and inflammatory burden, thus preventing endothelial dysfunction.

in conclusion

Endothelial dysfunction-induced endotheliitis during SARS-CoV-2 infection occurs by several pathophysiological mechanisms, either directly by SARS-CoV-2 disease or indirectly by paracrine effects of virus-infected cells. increase. Current therapies for COVID-19 focus on inhibiting viral replication and limiting inflammasome activation or inflammation, whereas novel therapeutic strategies for endothelial dysfunction may be needed in convalescent heart disease. It may be promising for vascular sequelae.