Endothelial dysfunction in COVID-19

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Emerging evidence suggests that SARS-CoV-2 infection leads to multiple instances of endothelial dysfunction and causes:
 
-reduced nitric oxide (NO) bioavailability,
-oxidative stress, endothelial injury,
-glycocalyx/barrier disruption,
-hyperpermeability,
-inflammation/leukocyte adhesion,
-senescence,
-endothelial-to-mesenchymal transition (EndoMT),
-hypercoagulability,
-thrombosis

The fight against coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is still raging. However, the pathophysiology of acute and post-acute manifestations of COVID-19 (long COVID-19) is understudied. Endothelial cells are sentinels lining the innermost layer of blood vessel that gatekeep micro- and macro-vascular health by sensing pathogen/danger signals and secreting vasoactive molecules.

SARS-CoV-2 infection primarily affects the pulmonary system, but accumulating evidence suggests that it also affects the pan-vasculature in the extrapulmonary systems by directly (via virus infection) or indirectly (via cytokine storm), causing endothelial dysfunction (endotheliitis, endothelialitis and endotheliopathy) and multi-organ injury.

Mounting evidence suggests that SARS-CoV-2 infection leads to multiple instances of endothelial dysfunction, including reduced nitric oxide (NO) bioavailability, oxidative stress, endothelial injury, glycocalyx/barrier disruption, hyperpermeability, inflammation/leukocyte adhesion, senescence, endothelial-to-mesenchymal transition (EndoMT), hypercoagulability, thrombosis and many others. Thus, COVID-19 is deemed as a (micro)vascular and endothelial disease. Of translational relevance, several candidate drugs which are endothelial protective have been shown to improve clinical manifestations of COVID-19 patients.

The purpose of this review is to provide a latest summary of biomarkers associated with endothelial cell activation in COVID-19 and offer mechanistic insights into the molecular basis of endothelial activation/dysfunction in macro- and micro-vasculature of COVID-19 patients.

We envisage further development of cellular models and suitable animal models mimicking endothelial dysfunction aspect of COVID-19 being able to accelerate the discovery of new drugs targeting endothelial dysfunction in pan-vasculature from COVID-19 patients.

The review was published in the peer reviewed journal: Acta Pharmacologica Sinica (By Nature)
https://www.nature.com/articles/s41401-022-00998-0

SARS-CoV-2 infection alters the balance of endothelial protective molecules and endothelial damaging molecules, leading to endothelial dysfunction. ADMA asymmetrical dimethylarginine, AngII angiotensin II, Angpt-2 angiopoietin-2, CAT catalase, EDHF endothelium-derived hyperpolarizing factor, eNOS endothelial nitric oxide synthase, ET-1 endothelin 1, GCH1 GTP cyclohydrolase 1, H2S hydrogen sulfide, HO-1 heme oxygenase-1, ICAM1 intercellular adhesion molecule 1, KLF2 krüppel-like factor 2, NO nitric oxide, Nrf2 nuclear factor erythroid 2-related factor 2, PAI-1 plasminogen activator inhibitor 1, PGI2 prostaglandin I2, ROS reactive oxygen species, SOD superoxide dismutase, TF tissue factor, Thbd thrombomodulin, Tie-2 tyrosine-protein kinase receptor, tPA tissue plasminogen activator, Tx-A2 thromboxane A2, uPA urokinase plasminogen activator, VCAM1 vascular cell adhesion molecule 1, vWF von Willebrand factor.

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Endothelial function and dysfunction
The endothelium, the widely-distributed organ of the human body, is essential for maintaining tissue homeostasis by producing a variety of vasoactive molecules. These vasoactive molecules tightly control the fine balance between vasodilatory and vasoconstrictory, pro-proliferative and anti-proliferative, pro-thrombotic and anti-thrombotic, pro-oxidant and antioxidant, fibrinolytic and anti-fibrinolytic, and pro-inflammatory and anti-inflammatory responses (Fig. 1). Physiological functions of the vascular endothelium include: (1) maintenance of barrier integrity; (2) regulation of vascular tone; (3) regulation of hemostasis; (4) maintenance of an anti-inflammatory, anti-oxidant and anti-thrombotic interface; (5) regulation of anti-proliferative properties, and (6) regulation of cellular metabolism of ATP, glucose, amino acids, etc. Among these physiological functions, nitric oxide (NO) represents the key mechanism for maintaining endothelial homeostasis [2, 15].

NO is one of the most important vasodilatory substances produced by the vascular endothelium with the action of the endothelial NO synthase (eNOS) and several cofactors. NO also has an anti-thrombotic action, by preventing leukocyte and platelet adhesion to activated endothelium, thereby inhibiting immunothrombosis and atherosclerotic plaque development [15].

Endothelial dysfunction is generally defined as decreased NO bioavailability and an increase in vasoconstrictory substances (such as endothelin-1 (ET1), angiotensin II (Ang II) and many others). The decrease of NO bioavailability occurs partially because of a decrease in eNOS-derived NO production and enormous production of reactive oxygen species (ROS), which inactivates eNOS and causes eNOS uncoupling. ECs are also capable of counteracting ROS, by increasing superoxide dismutase (SOD), catalase, glutathione peroxidase, and NRF2-dependent heme-oxygenase 1 expression [2]. Contemporary definition of endothelial dysfunction has been extended to a constellation of cellular events including oxidative stress, inflammation/leukocyte adhesion, EndoMT, mitochondria dysfunction, senescence and deregulated endothelial cell metabolism [15].

Endothelial dysfunction and COVID-19 associated multi-organ injury
COVID-19 can present with multiple manifestations arising from endothelial dysfunction/endotheliopathy as below (Fig. 2) [2, 16].

Direct SARS-CoV-2 infection or indirect effect arising from SARS-CoV-2 infection leads to endothelial dysfunction in pan-vasculature, which results in the development of multi-organ tissue injury. SASP senescence-associated secretory phenotype.

Acute lung injury
According to the American-European Consensus Conference on acute respiratory distress syndrome (ARDS), the ARDS is the most severe form of the acute lung injury [17] as well as ongoing COVID-19 associated lethality [18]. Pulmonary capillary endothelium provides a fertile “soil” for viral entry, replication, thereby facilitating viral entry to the circulating blood [19, 20]. SARS-CoV-2 infects the ECs and epithelial cells in lung tissues via angiotensin-converting enzyme-2 (ACE2) and alternative receptors [21] on host cells [22].

Interestingly, live SARS-CoV-2 virus and sera from COVID-19 patients, but not dead virus or spike protein triggers increased endothelial permeability [20, 23]. Endothelial integrity is essential for maintaining the pulmonary capillary-alveolar barrier and lung homoeostasis. COVID-19 is associated with pervasive ECs injury, increased capillary permeability, infiltration of inflammatory cells into perivascular tissues, interstitial edema and fluid retention in alveolar spaces [19]. In addition, the release of inflammatory cytokines after severe SARS-CoV-2 infection leads to cytokine storm, tight junction barrier disruption, pulmonary hypertension, and lung fibrosis [24]. Therefore, emerging therapies targeting endothelial dysfunction and endotheliopathy are hopeful to ameliorate COVID-19 associated lung injury [25].

Myocardial injury and myocardial infarction
While COVID-19 primarily affects the lungs, it also affects other organs, the heart in particular. Mortality of COVID-19 patients is increased by comorbidities of cardiovascular disease and hypertension in particular. The most common cardiovascular complications of COVID-19 include arrhythmia, cardiac injury (evidenced by elevated troponin I, creatine kinase, NT-proBNP levels), coagulation (evidenced by elevated level of D-dimer), fulminant myocarditis, heart failure and new-onset atherosclerosis [26]. In these cardiovascular complications, endothelial dysfunction plays a fundamental role [27].

Mechanistically, patients with heart failure demonstrate increased ACE2 gene and protein expression, suggesting that if patients with heart failure were infected by the virus, they are more susceptible to severe COVID-19 and develop into a critically-ill conditions [28]. In addition, COVID-19 is an important risk factor for developing acute myocardial infarction [29]. Data from multi-center registry support that ST-segment elevation myocardial infarction (STEMI) patients enrolled during the first-wave of COVID-19 experience longer time of ischemia and a higher rate of adverse events [30, 31], suggesting the need for COVID-19 vaccines.

However, data from a small study cohort demonstrate that the majority of patients with acute myocardial infarction developed symptoms after COVID-19 vaccinations [32]. Since atherosclerosis is an important cause for coronary artery disease, it might be of interest to investigate whether COVID-19 can accelerate the development of endothelial dysfunction and new onset atherosclerosis [26]. In addition, we need to screen for atherosclerotic plaque formation in COVID-19 survivors, as there are no actual clinical data providing the causal relationship between COVID-19 and atherosclerosis.

Liver injury
COVID-19 is also associated with liver injury. By using high-resolution confocal microscopy, a recent study has detected the existence of SARS-CoV-2 viral proteins within the liver sinusoidal endothelial cells (LSECs) from COVID-19 patient liver tissues [33]. In addition, C-type lectin receptor L-SIGN, a receptor highly expressed on LSECs and lymphatic endothelial cells, was identified as the receptor for SARS-CoV-2 infection and may contribute to endotheliopathy in the liver [33].

After virus infection, ensuing cytokine storm occurs in severe COVID-19 patients, particularly the elevated secretion of pro-inflammatory cytokine interleukin 6 (IL-6). Recent studies have suggested that LSEC dysfunction is involved in COVID-19 associated liver injury [34]. A recent study [35] has reported that IL-6 trans-signaling in LSECs leads to endotheliopathy and liver injury in COVID-19 patients. The authors observed elevated levels of markers of coagulopathy/endotheliopathy and liver injury (ALT) in COVID-19 patients. Correlation analysis indicates that the level of IL-6 positively correlated with the level of markers of endothelial activation (vWF, factor VIII, and D-dimer). Activation of IL-6 trans-signaling in LSECs leads to coagulopathy, elevation of pro-inflammatory factors, and platelet adhesion to LSECs. These effects were blocked by soluble glycoprotein 130, ruxolitinib, and STAT1/3 depletion. Therefore, IL-6 trans-signaling represents the mechanistic link between the coagulopathy/endotheliopathy and COVID-19 associated liver injury [35]. The effects and molecular mechanism of COVID-19 on chronic liver injury require detailed further studies [36].

Kidney injury
SARS-CoV-2 infection can also cause acute kidney injury (AKI). A recent multi-omics study has revealed that COVID-19 associated AKI resembles AKI induced by sepsis, which involves the mechanism of mitochondria dysfunction, inflammation, necroptosis, capillary congestion and endothelial injury [37]. ACE2 is highly expressed in renal tissues, the injury of which leads to proteinuria, hematuria and abnormal renal radiography [38]. Like other types of organ injury, SARS-CoV-2 infection causes AKI by both direct and indirect mechanisms, including endotheliitis, thrombosis and glucolipid derangement.

Other injuries
In addition to the above-mentioned organ injuries, COVID-19 also leads to neuropathy [39], redox imbalance and mitochondria dysfunction which may underlie neurological complications of COVID-19 [40]. SARS-CoV-2 can cross the blood brain barrier without affecting the expression of tight junctions (claudin5, ZO-1 and occludin) [41]. It is noted that even in convalescent COVID-19 patients undergoing rehabilitation, cognitive impairment and endothelial dysfunction still exist, indicating the necessity to monitor endothelial dysfunction in convalescent patients [42]. COVID-19 is also associated with acute limb ischemia [43], reproductive system injury, such as erectile dysfunction [44], stroke and deep vein thrombosis [11].

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