October 1, 2020

Is COVID-19 a vascular disease?

COVID-19 is currently challenging for the global health system. The main cause of mortality in patients infected with the SARS-CoV-2 coronavirus is respiratory failure caused by acute respiratory distress syndrome (ARDS). But why is it? Recent studies suggest that pulmonary complications are the result of an alteration of the blood vessels.

Endothelial cells involved

The interior of the blood vessels is lined by a single layer of endothelial cells. Although until recently it was thought that the endothelium simply performed the work of lining the pipelines through which the blood circulates, the truth is that we were underestimating it. Research carried out in recent decades has revealed its role in a multitude of functions, including the control of arterial tone, fibrinolysis and vascular growth. To make matters worse, under physiological conditions the endothelium prevents inflammation and prevents the formation of blood clots.

Taking this into account, it is understood why the alteration of the endothelium is expensive. Specifically, it is involved in various pathologies of a vascular nature, such as atherosclerosis, coronary vasoconstriction, and myocardial ischemia, among others.

And what about COVID-19? Until a few months ago, lung endothelial cells were not even thought to be related to the disease. But recent studies reveal her key role in the initiation and subsequent spread of ARDS. Specifically, endothelial cells appear to alter the integrity of the vascular barrier in SARS-CoV-2 coronavirus infection. That would lead to tissue edema (accumulation of fluid in the lungs), inflammation of the endothelium (endotheliitis), activation of the coagulation pathways, and uncontrolled infiltration of inflammatory cells.

Clarifying the relationship between endothelial cells, viral infection, and inflammatory and pro-thrombotic changes associated with COVID-19 is of vital importance in developing new therapeutic strategies. Especially for that 30% of hospitalized patients with COVID-19 who develop a serious disease with progressive lung damage.

COVID-19 also attacks blood vessels

The first scientific evidence that the SARS-CoV-2 coronavirus infected endothelial cells was published last March in the medical journal The Lancet by Dr. Zsuzsanna Varga and her colleagues at the University Hospital of Zurich (Switzerland). Puzzled when observing in COVID-19 patients various symptoms not attributable to a respiratory infection, such as damage to vital organs and thrombus formation, they analyzed tissues from patients who died in the pandemic under the microscope.

The results, although surprising, were very revealing. They showed that SARS-CoV-2 had infected patients’ endothelial cells, inflaming both respiratory tissue and the endothelium of other vital organs. Which explained the fatal and rapid outcome in these patients.

Following the publication of this article, many groups have detected similar patterns of vascular damage in victims of COVID-19. Everything indicates that the effects of the virus on the endothelium would explain the serious forms of COVID-19 in patients belonging to populations not considered “at risk”, such as apparently healthy children and young people. These people, they say, could have an undiagnosed vascular or endothelial disorder that would amplify the effects of the infection.

An explanation for multi-organ failure

Peter Carmeliet, a leading Belgian researcher in the field of vascular biology, has used these studies and his own laboratory experiments to develop a hypothesis of how the SARS-CoV-2 coronavirus attacks the endothelium and triggers the multiorgan failure observed in some patients.

As explained last May in the prestigious magazine Nature Reviews Immunology, COVID-19 would progress in several phases:

  1. In the first, as soon as the viral infection occurs, SARS-CoV-2 binds to ACE2 receptor and infects the endothelial cells of the pulmonary capillaries. This affects the integrity of the endothelium and increases vascular permeability. Endothelial damage causes blood vessels to become more patent, promoting the appearance of pulmonary edema and respiratory failure.
  2. Then, white blood cells they are directed towards the “activated” pulmonary endothelium. The signaling molecules, generated by both the endothelium and the cells of the immune system that flock, would increase the damage done to the cells of the lung tissue. Some of those cells may even “commit suicide,” initiating a process called apoptosis.
  3. To make matters worse, direct damage to the endothelium can be accompanied by other serious indirect consequences. Without going any further, the alteration of the junctions between the endothelial cells can trigger a uncontrolled blood clotting. On the other hand, obstruction of the small capillaries by inflammatory cells, together with possible thrombosis in larger vessels, can cause ischemia (decreased blood flow) in the lung tissue, and even give rise to what is known as “Cytokine storm”.
The Conversation

Although inflammation and coagulation are essential defense mechanisms in the body, in COVID-19 its uncontrolled hyperactivation can cause irreversible and lethal damage to the patient.

What has been described so far could also explain why diabetes, high blood pressure and obesity are an important risk factor. In all three diseases the endothelium is damaged.

Treatments targeting the endothelium

Once the decisive role of endothelial cells in the most serious forms of COVID-19 has been confirmed, it is urgent to develop therapeutic strategies that protect it. In this direction, there are already pathophysiological foundations for using statins as an adjunctive treatment. Statins, present in the medicine cabinet of many houses, are known for their stabilizing effect on the endothelium and their ability to lower cholesterol, prevent clotting and prevent plaque formation in the arteries.

In addition, clinical trials are underway with various treatments to correct endothelial dysfunction. This is the case of drugs directed against angiopoietin-2, a protein involved in the generation of new blood vessels. Or bevacizumab, an antibody that can block uncontrolled activation of endothelial cells.

Although it is still early to have a definitive answer, everything points to the fact that treatments that avoid endothelial damage could be beneficial for COVID-19 sufferers.

Melissa García Caballero is ipostdoctoral researcher at the University of Malaga and Ana Rodríguez Quesada is cProfessor of Biochemistry and Molecular Biology at the University of Malaga.

This article was originally published in The Conversation. You can read the original here.


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