Is the Endothelium the Missing Link in the Pathophysiology and Treatment of COVID-19 Complications?

Abstract

Patients with COVID-19 present a wide spectrum of disease severity, from asymptomatic cases in the majority to serious disease leading to critical care and even death. Clinically, four different scenarios occur within the typical disease timeline: first, an incubation and asymptomatic period; second, a stage with mild symptoms due mainly to the virus itself; third, in up to 20% of the patients, a stage with severe symptoms where a hyperinflammatory response with a cytokine storm driven by host immunity induces acute respiratory distress syndrome; and finally, a post-acute sequelae (PASC) phase, which present symptoms that can range from mild or annoying to actually quite incapacitating. Although the most common manifestation is acute respiratory failure of the lungs, other organs are also frequently involved. The clinical manifestations of the COVID-19 infection support a key role for endothelial dysfunction in the pathobiology of this condition. The virus enters into the organism via its interaction with angiotensin-converting enzyme 2-receptor that is present prominently in the alveoli, but also in endothelial cells, which can be directly infected by the virus. Cytokine release syndrome can also drive endothelial damage independently. Consequently, a distinctive feature of SARS-CoV-2 infection is vascular harm, with severe endothelial injury, widespread thrombosis, microangiopathy, and neo-angiogenesis in response to endothelial damage. Therefore, endothelial dysfunction seems to be the pathophysiological substrate for severe COVID-19 complications. Biomarkers of endothelial injury could constitute strong indicators of disease progression and severity. In addition, the endothelium could represent a very attractive target to both prevent and treat these complications. To establish an adequate therapy, the underlying pathophysiology and corresponding clinical stage should be clearly identified. In this review, the clinical features of COVID-19, the central role of the endothelium in COVID-19 and in other pathologies, and the potential of specific therapies aimed at protecting the endothelium in COVID-19 patients are addressed.

Peripheral microcirculatory alterations are associated with the severity of acute respiratory distress syndrome in COVID-19 patients admitted to intermediate respiratory and intensive care units

“…Several mechanisms have been proposed to contribute to ED, including direct endothelial cell damage produced by the virus, down-regulation of the angiotensin-converting enzyme 2 (ACE2) receptors, the inflammatory response of the host, or even as a results of tissue hypoxia in the setting of severe hypoxemia, among others [ 17 – 23 ]. Some authors suggest that COVID-19 might be considered an endothelial disease [ 8 , 19 , 20 ], and those patients with more severe forms, probably due to individual predisposition, will develop not only respiratory disease, but also systemic disease, with generalized ED, coagulopathy, disseminated intravascular coagulation (DIC), and multi-organ failure [ 22 , 23 ]. Our study does not provide insights in the mechanisms of ED, but confirms that microvascular reactivity, as a surrogate of endothelial function, can be properly evaluated and monitored in severe COVID-19 patients by means of non-invasive near-infrared spectroscopy technologies.…”

“…Sedation (deep sedation) might appear as one of the causes of altered microcirculation in COVID, but we already observed equivalent alterations in awake patients receiving HFNC or Venturi mask, without apparent cardiovascular problems. To date, microcirculatory impairment has been extensively associated with hemodynamic alterations, such as in septic shock [ 8 – 10 ]. Of note, none of the studied patients showed increased plasma lactate levels, and only twelve patients were receiving vasopressors for maintaining adequate blood pressure values.…”

“…Postmortem examinations have shown three main features at the vascular level: (I) endothelial damage, with both viral inclusions and endothelial inflammation including monocellular cell infiltrate and lymphocytic endotheliitis; (II) extensive vascular thrombosis; and (III) abnormal vascular architecture [ 6 , 7 ]. Consequently, monitoring endothelial function emerges as a potential biomarker of COVID-19 severity for prognostic purposes or monitoring the effect of new treatment options [ 8 , 9 ].…”

Resveratrol as an Adjunctive Therapy for Excessive Oxidative Stress in Aging COVID-19 Patients

“…However, endothelial dysfunction could also occur secondarily to the activation of either inflammatory, coagulation and complement cascades, or in combination [32]. As a result, the endothelial lesions caused by COVID-19 are at the crossroads of hypercoagulation, fibrinolysis impairment, complement system activation, and glycocalyx layer degradation [33].…”

COVID-19 Associated Choroidopathy

“…Risk factors for morbidity and mortality of COVID-19 infection include coronary heart disease (CHD), hypertension, diabetes, male sex, smoking and obesity [2][3][4][5]. SARS-CoV2 penetrates the human cells by binding to the angiotensin-converting enzyme-2 (ACE-2) receptor which is present in the lungs and is highly expressed in the vascular endothelium [6]. SARS-CoV2 is responsible for multi-organ damages, either by direct virus attack or indirectly by inappropriate activation of the immune system and of both the complement and the coagulation cascade [7].…”