COVID-19 is currently challenging the global healthcare system. The main cause of mortality in patients infected by 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 a disturbance 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 was simply lining the pipes 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, among which the control of arterial tone, fibrinolysis and vascular growth stand out. As if that were not enough, 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, it was not even considered that lung endothelial cells were related to the disease. But recent studies reveal its key role in the initiation and subsequent spread of ARDS. Specifically, it appears that in infection by the SARS-CoV-2 coronavirus, endothelial cells alter the integrity of the vascular barrier. This would lead to tissue edema (accumulation of fluid in the lungs), inflammation of the endothelium (endothelitis), activation of the clotting 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 to develop new therapeutic strategies. Especially for those 30% of hospitalized COVID-19 patients who develop a serious illness 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 from the University Hospital of Zurich (Switzerland). Surprised to observe 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, while surprising, were very revealing. They showed that SARS-CoV-2 had infected the 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 COVID-19 victims. 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 suffer from an undiagnosed endothelial or vascular 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 drawn on these studies and his own laboratory experiments to hypothesize how the SARS-CoV-2 coronavirus attacks the endothelium and triggers the multi-organ failure observed in some patients.
As explained last May in the prestigious journal Nature Reviews Immunology , COVID-19 would progress in several phases:
In the first, as soon as the viral infection occurs, SARS-CoV-2 binds to the 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 permeable, promoting pulmonary edema and respiratory failure.
The white blood cells then travel to the “activated” lung endothelium. The signaling molecules, generated both by the endothelium and by the cells of the immune system that flock, would increase the damage produced on the cells of the lung tissue. Some of these cells could even “commit suicide”, initiating a process called apoptosis.
To add insult to injury, direct damage to the endothelium can be accompanied by other serious indirect consequences. Without going any further, disruption of the junctions between endothelial cells can trigger uncontrolled blood clotting. On the other hand, the obstruction of 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.”
Although inflammation and clotting 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 to make use of statins as 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 the formation of plaques 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 the uncontrolled activation of endothelial cells.
Although it is still too early to have a definitive answer, everything indicates that treatments that prevent endothelial damage could be beneficial for COVID-19 patients.
Melissa García Caballero, postdoctoral researcher, University of Málaga and Ana Rodríguez Quesada, professor of Biochemistry and Molecular Biology, University of Málaga
This article was originally published on The Conversation. Read the original.
