The implications of COVID‐19 infection on the endothelium: A metabolic vascular perspective

Abstract

COVID-19 is a worldwide pandemic. Metabolic disorders, especially diabetes, hypertension and obesity are the most common comorbidities associated with severity of disease in COVID-19.1 Serious cardiovascular consequences including myocarditis, acute coronary syndromes, pulmonary embolism, stroke, arrhythmias, heart failure, cardiogenic shock and severe arterial thrombosis have been reported.2, 3 Abnormalities in the coronary microcirculation which can occur in the setting of diabetes and other metabolic disorders can also contribute to myocardial infarction even in the absence of obstructive coronary artery disease.4 Endothelial dysfunction is the harbinger of all metabolic disease related vascular complications. The endothelial cells line all the blood vessels in the body. We are all born with a quiescent endothelium wherein shear stress of the blood flow induces nitric oxide gas formation which induces vascular smooth muscle relaxation and flow mediated dilatation. During periods of infection the endothelium gets activated to incite an inflammatory response as part of the host innate or adaptive immune response with return to quiescent stage after resolution of infection.5, 6 In the presence of numerous environmental insults, diabetes, hypertension, hyperlipidaemia with advanced glycation end products or with reduced shear stress on the endothelium, it activates the reactive oxygen species formation with an increase in oxidative stress and further downstream activation of the molecular machinery leading to activation of inflammatory and thrombotic pathways in the endothelium. In chronic disorders, the persistent endothelial activation leads to endothelial dysfunction leading to stiffer, thicker vessels over time. At the same time, exacerbation of thrombotic pathways, leads to formation of plaques which has the ability to rupture and cause embolism.5-7 In the heart, peripheral arteries and cerebrovascular arteries these mechanisms lead to atherosclerosis and its manifestations. The impact and reactions of the endothelium is variable in different vascular beds. Endothelial injury which can incite angiogenic cytokines especially in small vessels with minimal capacity for vascular smooth muscle proliferation and thickening of basement membrane, and ability for disruption of tight and adherens junction, it can lead to sprouting and proliferation of endothelial cells, which forms lumens and with time are covered with mature vascular basement membrane leading to angiogenesis.8 Chronically in the eye, pathological neovascularization is a hallmark in several retinal degenerative diseases, including age-related macular degeneration. In age-related macular degeneration, it has been seen that acute mechanical stress and hypoxia among other factors can trigger increased expression of angiogenic factors, namely vascular endothelial growth factor (VEGF), angiotensin-II, hypoxia inducing factor: HIF-1α, interleukins: IL6, IL8 and tumour necrosis factor: TNF-α and these lead to angiogenesis and manifestations of disease.8 In retinal vessels and in the kidneys, in the presence of transforming growth factor-β1 (TGF-β), leucine-rich alpha-2-glycoprotein 1 (Lrg1), promotes angiogenesis. LRG1 binds directly to the endoglin, which, in the presence of TGF-β1, promotes the pro-angiogenic Smad1/5/8 signalling pathway and levels are higher in patients with diabetic kidney disease.9, 10 In the kidneys, once uraemia occurs, the process of immune dysregulation and downstream endothelial dysfunction and signalling pathways leads to an exacerbation with accelerated immune and vascular senescence.11 It is known that the SARS-CoV virus infects the hosts through angiotensin converting enzyme-2 (ACE-2) enzymes and transmembrane serine protease 2 (TMPRSS2) expressed in the alveolar cells. Other receptors used by the virus include sialic acid receptors, and extracellular matrix metalloproteinase inducer (CD147).12, 13 The receptor TMPRSS2 is also expressed in cardiac endothelial cells14 and CD147 is minimally expressed in normal vessels, but its expression increases following inflammation and vascular injury.15 In an autopsy study, a significantly greater number of ACE-2 positive endothelial cells with significant changes in the morphology has been reported. It is possible that through the use of ACE-2 the virus is causing unique and distinctive sequelae.16 The virus by itself has the potential to cause significant epithelial and endothelial injury. The ACE-2 receptors are also expressed in pericytes which communicate with endothelial cells via the angiopoietin ligands (ANGPT1/2). This dynamic interplay is vital for the endothelial cell survival.17 Viral invasion of pericytes potentially disrupts this milieu potentially increasing endothelial cell injury. In a recent histopathological study, the authors have reported endothelial cell involvement across vascular beds of different organs with severe lymphocytic endothelialitis, viral inclusion bodies and apoptosis of varying degrees in the lungs, heart, kidneys, liver and submucosal vessels of the intestines.18 Recent observational reports of higher frequency of Chilblains (‘COVID toes’) in children and young adults during the COVID-19 pandemic have also revealed the presence of Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) particles in the endothelial and epithelial cells of the eccrine glands and likely being causative.19 Consequentially, this virus has the potential to incite a significant inflammatory reaction. The infection requires both an innate immune response (in terms of neutrophils) and a strong adaptive immune response in terms of T cell response to control viral infection. An un-regulated extreme inflammatory response, in terms of a cytokine storm is associated with poor prognosis.20 The platelets are activated in COVID-19 and can contain SARS-CoV-2 RNA.21 Second, the ACE-2 and angiotensin-1-7 are counter regulators of ACE and are known to have a protective effect on endothelial function, and deletion of ACE-2 is associated with development of increased vascular thickening (neointima formation). Serum angiotensin-II levels in patients with COVID-19 pneumonia is significantly higher compared with healthy individuals and linearly associated with viral load and lung injury.22 The effects on the endothelium, due to the unchecked activity of angiotensin-II, through its activation of AT1R (angiotensin 1 receptor) on the endothelium can lead to vasoconstriction, vascular smooth muscle proliferation, endothelial activation and thrombosis.23 Third, angiotensin-II is a very potent stimulator of neo-angiogenesis through AT1R receptors and is required for choroidal neovascularisation and the neutrophilic response seen in COVID-19 with neutrophil extracellular traps,24 contributes to neoangiogenesis.5, 25 Fourth, angiotensin-II can get converted to angiotensin-IV with consequences of microvascular thrombosis especially in presence of an activated T cell response.26 Hence, the virus causes endothelial damage, inflammatory and T cell immune response, and unregulated activity of angiotensin-II. All these effects can accelerate downstream signalling of endothelial function pathways from inflammation, thrombosis to angiogenesis depending on the vascular bed affected. See Figure 1. Schema elaborating the endothelial dysfunction pathways in diabetes, COVID-19 Infections and potential areas of exacerbation in diabetes Recently, autopsy studies have also highlighted an increased risk of arterial and venous thromboembolism in COVID-19 patients. Distinctively, it has been seen that the main differences in COVID-19 infection for the pulmonary vessels is severe endothelialiitis or endothelial injury and widespread thrombosis, and intussusceptive angiogenesis.7 This angiogenesis phenomenon is very similar to the one seen in patients with choroidal neovascularisation in acute macular degeneration in the initial stages before sprouting angiogenesis occurs.5 A recent Genome wide association study identified the locus 3p21.31 with gene cluster: SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6 and XCR1 and locus 9q34.2 coinciding with ABO blood group, as genetic susceptibility locus for respiratory failure in COVID-19. SLC6A20, which encodes the sodium–amino acid (proline) transporter 1 functionally interacts with ACE-2 and has been seen to be co-located in the enterocytes and kidney tubules with similar regulatory mechanisms.27 CCR9 and CXCR6 encodes chemokine receptors which are responsible for the immune response seen.27 A lower susceptibility was seen for the blood group O which may be mediated through a decrease in thrombosis potential through lower von-Willebrand factor levels especially in pulmonary endothelial cells.28 Hence since many of these genetic associations are linked to the endothelium, these pathways need to be evaluated further. There have been reports of multisystem inflammatory syndrome in children, similar but more pronounced with higher rates of cardiovascular involvement than Kawasaki's disease.29-32 The major pathologic feature is acute systemic vasculitis with coronary artery dilatation in the first 4 weeks. The hallmark of the vasculitis is endothelial cell oedema, proliferation, necrosis and adhesion of polymorphonuclear leukocytes to endothelium. These events are accompanied by marked immune activation, characterized by increasing levels of circulating cytokines, CD4 and CD8 cells, polyclonal hypergammaglobulinemia, and circulating IgG and IgM immunocomplexes.33 Kawasaki disease usually resolves spontaneously but may lead to serious complications, including coronary artery disease, if left untreated. Although rare, Kawasaki's disease has been reported in adults as well and these reports highlights a possibility of similar mechanism in adults occurring with COVID-19 infection, which may remain un-noticed leading to risks of cardiovascular complications and exacerbation of pre-existing coronary artery disease.33 Patients with diabetes are at a higher risk as the expression of the receptors like CD147 which facilitates viral entry into the endothelial cells may be higher due to pre-existing vascular injury.15 Moreover, the angiotensin II concentrations and the subsequent pathways are known to be higher in these patients. They already have a chronically activated endothelium and especially fluctuating glucose concentrations are known to lead to a higher rate of endothelial cell apoptosis, induce endothelial cytokine production, increase expression of endothelial markers (VCAM-1, ICAM-1,VEGF,IL-B, NF-κB and E-selectin) and increase monocyte adhesion.34, 35 Pre-existing endothelial activated state has the potential to exacerbate the cytokine storm associated with more severe COVID-19 and allow the uncontrolled extravasation of neutrophils into the alveolus and other sites leading to multi-organ failure. These observations has brought the endothelium into focus as one of the pathogenetic causes of severe disease manifestations in COVID-19 and is being cross labelled as ‘endothelial disease’. Understanding the exact mechanisms may help to develop novel treatment approaches. Theoretically the effects of infection with SARS-CoV-2 mimics the classical endothelial dysfunction pathway in microvascular and macrovascular dysfunction seen in diabetes. There is considerable speculation that the main reason for worse prognosis in patients with hypertension and diabetes is the underlying vascular dysfunction which gets exacerbated with COVID-19 infection. Use of medications that can be used to stabilise the endothelial function, for example, statins, anti-inflammatory agents, anti-cytokine agents such as toclizumab and other forms of immune modulation such as interleukin-6 blockers have been proposed to limit the effects of disease.36, 37 In view of this similarity, there would be a concern of acceleration of this molecular machinery to some degree even in recovered COVID-19 patients with underlying diabetes and metabolic disorders. Hence, clinically, it would be crucial to follow up the recovered patients with underlying metabolic disorders very closely for development of microvascular and macrovascular complications in all the vascular beds especially the eyes, kidneys and the heart. We also need to consider a close evaluation and follow up of other endocrine organ systems which are known to show a high level of expression of ACE2 positive cells and organ systems known to harbour an (autoregulated) regulated blood flow such as small intestine (micronutrient absorption),38 testis (male reproductive hormones),37 ovaries (female reproductive hormones)39 and thyroid gland (development of neoplastic lesions or functional problems).40 Particular attention needs to be given to patients at high risk for ischaemic heart disease. Emergency physicians and cardiologists need to have a low threshold for admission and screening even for non-specific cardiac symptoms in these patients. Proactive screening for patients with diabetes with possible underlying silent ischaemic heart disease needs to be considered as well. Further evidence is required on the occurrence of vascular, metabolic and endocrine problems in COVID-19 recovered patients in the long term. The authors thank Ministry of Health for the Clinician Scientist Award (MOH-000014) and National Medical Research Council Centre Grant (NMRC/CG/017/2013) for supporting RD and Ong Tiong Tat Foundation for supporting BOB. The authors declare no competing interests. Rinkoo Dalan and Bernhard O. Boehm conceived the idea, wrote the manuscript, reviewed and approved the final manuscript. Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

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