Research progress on the regulation of endothelial cells by natural products of traditional Chinese medicine in the prevention and treatment of atherosclerosis

[] Atherosclerosis (As) is the pathological basis of coronary heart disease, and vascular endothelial injury is the initiating factor of coronary atherosclerosis. Vascular endothelial cells are a single layer of cells located in the inner layer of blood vessels and regulates exchanges between the blood stream and the surrounding tissues, and their integrity is very important. Many active monomers and the derivatives in natural products of traditional Chinese medicine modulate the function of endothelial cells by intervening oxidative stress, regulating the release of vasoactive substances, reducing inflammation, and equilibrating coagulation and anticoagulant system. They have the advantages of multi-pathway, multi-link and multi-target regulation in protecting from endothelial injury and attenuating atherogenesis. They have also been used to protect against corona virus disease 2019 (COVID-19) induced endothelial injury and atheroslerosis. This article reviews the research progress of the above issues in this field. © 2023, Editorial Office of Chinese Journal of Arteriosclerosis. All rights reserved.

IDDF2023-ABS-0045 Spatiotemporal immune landscape of Mas-driven pro-inflammatory microenvironment with hyperactivated glycolysis in acetaminophen-induced liver injury

IDDF2023-ABS-0045 Figure 1 IDDF2023-ABS-0045 Figure 2 IDDF2023-ABS-0045 Figure 3 IDDF2023-ABS-0045 Figure 4

Synergistic effect of elevated glucose levels with SARS-CoV-2 spike protein induced NOX-dependent ROS production in endothelial cells.

BACKGROUND: Diabetic patients infected with coronavirus disease 2019 (COVID-19) often have a higher probability of organ failure and mortality. The potential cellular mechanisms through which blood glucose exacerbates tissue damage due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is still unclear. METHODS AND RESULTS: We cultured endothelial cells within differing glucose mediums with an increasing concentration gradient of SARS-CoV-2 Spike protein (S protein). S protein can cause the reduction of ACE2 and TMPRSS2, and activation of NOX2 and NOX4. A high glucose medium was shown to aggravate the decrease of ACE2 and activation of NOX2 and NOX4 in cultured cells, but had no effect on TMPRSS2. S protein mediated activation of the ACE2-NOX axis induced oxidative stress and apoptosis within endothelial cells, leading to cellular dysfunction via the reduction of NO and tight junction proteins which may collectively be exacerbated by elevated glucose. In addition, the glucose variability model demonstrated activation of the ACE2-NOX axis in a similar manner observed in the high glucose model in vitro. CONCLUSIONS: Our present study provides evidence for a mechanism through which hyperglycemia aggravates endothelial cell injury resulting from S protein mediated activation of the ACE2-NOX axis. Our research thus highlights the importance of strict monitoring and control of blood glucose levels within the context of COVID-19 treatment to potentially improve clinical outcomes.

Exosomal miR-145 and miR-885 regulate thrombosis in COVID-19.

We hypothesized that exosomal microRNAs (miRNAs) could be implied in the pathogenesis of thromboembolic complications in COVID-19. We isolated circulating exosomes from COVID-19 patients and then we divided our population in two arms based on the D-dimer level on hospital admission. We observed that exosomal miR-145 and miR-885 significantly correlate with D-Dimer levels. Moreover, we demonstrate that human endothelial cells express the main cofactors needed for SARS-CoV-2 internalization, including ACE2, TMPRSS2, and CD-147. Interestingly, human endothelial cells treated with serum from COVID-19 patients release significantly less miR-145 and miR-885, exhibit increased apoptosis, and display significantly impaired angiogenetic properties compared to cells treated with non-COVID-19 serum. Taken together, our data indicate that exosomal miR-145 and miR-885 are essential in modulating thromboembolic events in COVID-19. Significance Statement In this work, we demonstrate for the first time that two specific microRNA (namely miR-145 and miR-885) contained in circulating exosomes are functionally involved in thromboembolic events in COVID-19. Our findings are especially relevant to the general audience when considering the emerging prominence of post-acute sequelae of COVID-19 systemic manifestations known as Long-COVID.

ACE-2, TMPRSS2, and Neuropilin-1 Receptor Expression on Human Brain Astrocytes and Pericytes and SARS-CoV-2 Infection Kinetics.

Angiotensin Converting Enzyme 2 (ACE-2), Transmembrane Serine Protease 2 (TMPRSS-2) and Neuropilin-1 cellular receptors support the entry of SARS-CoV-2 into susceptible human target cells and are characterized at the molecular level. Some evidence on the expression of entry receptors at mRNA and protein levels in brain cells is available, but co-expression of these receptors and confirmatory evidence on brain cells is lacking. SARS-CoV-2 infects some brain cell types, but infection susceptibility, multiple entry receptor density, and infection kinetics are rarely reported in specific brain cell types. Highly sensitive Taqman ddPCR, flow-cytometry and immunocytochemistry assays were used to quantitate the expression of ACE-2, TMPRSS-2 and Neuropilin-1 at mRNA and protein levels on human brain-extracted pericytes and astrocytes, which are an integral part of the Blood-Brain-Barrier (BBB). Astrocytes showed moderate ACE-2 (15.9 ± 1.3%, Mean ± SD, n = 2) and TMPRSS-2 (17.6%) positive cells, and in contrast show high Neuropilin-1 (56.4 ± 39.8%, n = 4) protein expression. Whereas pericytes showed variable ACE-2 (23.1 ± 20.7%, n = 2), Neuropilin-1 (30.3 ± 7.5%, n = 4) protein expression and higher TMPRSS-2 mRNA (667.2 ± 232.3, n = 3) expression. Co-expression of multiple entry receptors on astrocytes and pericytes allows entry of SARS-CoV-2 and progression of infection. Astrocytes showed roughly four-fold more virus in culture supernatants than pericytes. SARS-CoV-2 cellular entry receptor expression and "in vitro" viral kinetics in astrocytes and pericytes may improve our understanding of viral infection "in vivo". In addition, this study may facilitate the development of novel strategies to counter the effects of SARS-CoV-2 and inhibit viral infection in brain tissues to prevent the spread and interference in neuronal functions.

Single-cell transcriptomic atlas of lung microvascular regeneration after targeted endothelial cell ablation.

We sought to define the mechanism underlying lung microvascular regeneration in a model of severe acute lung injury (ALI) induced by selective lung endothelial cell ablation. Intratracheal instillation of DT in transgenic mice expressing human diphtheria toxin (DT) receptor targeted to ECs resulted in ablation of >70% of lung ECs, producing severe ALI with near complete resolution by 7 days. Using single-cell RNA sequencing, eight distinct endothelial clusters were resolved, including alveolar aerocytes (aCap) ECs expressing apelin at baseline and general capillary (gCap) ECs expressing the apelin receptor. At 3 days post-injury, a novel gCap EC population emerged characterized by de novo expression of apelin, together with the stem cell marker, protein C receptor. These stem-like cells transitioned at 5 days to proliferative endothelial progenitor-like cells, expressing apelin receptor together with the pro-proliferative transcription factor, Foxm1, and were responsible for the rapid replenishment of all depleted EC populations by 7 days post-injury. Treatment with an apelin receptor antagonist prevented ALI resolution and resulted in excessive mortality, consistent with a central role for apelin signaling in EC regeneration and microvascular repair. The lung has a remarkable capacity for microvasculature EC regeneration which is orchestrated by newly emergent apelin-expressing gCap endothelial stem-like cells that give rise to highly proliferative, apelin receptor-positive endothelial progenitors responsible for the regeneration of the lung microvasculature.

Marked elevations in lung and plasma ceramide in COVID-19 linked to microvascular injury.

The pathogenesis of the marked pulmonary microvasculature injury, a distinguishing feature of COVID-19 acute respiratory distress syndrome (COVID-ARDS), remains unclear. Implicated in the pathophysiology of diverse diseases characterized by endothelial damage, including ARDS and ischemic cardiovascular disease, ceramide and in particular palmitoyl ceramide (C16:0-ceramide) may be involved in the microvascular injury in COVID-19. Using deidentified plasma and lung samples from COVID-19 patients, ceramide profiling by mass spectrometry was performed. Compared with healthy individuals, a specific 3-fold C16:0-ceramide elevation in COVID-19 patient plasma was identified. Compared with age-matched controls, autopsied lungs of individuals succumbing to COVID-ARDS displayed a massive 9-fold C16:0-ceramide elevation and exhibited a previously unrecognized microvascular ceramide-staining pattern and markedly enhanced apoptosis. In COVID-19 plasma and lungs, the C16-ceramide/C24-ceramide ratios were increased and reversed, respectively, consistent with increased risk of vascular injury. Indeed, exposure of primary human lung microvascular endothelial cell monolayers to C16:0-ceramide-rich plasma lipid extracts from COVID-19, but not healthy, individuals led to a significant decrease in endothelial barrier function. This effect was phenocopied by spiking healthy plasma lipid extracts with synthetic C16:0-ceramide and was inhibited by treatment with ceramide-neutralizing monoclonal antibody or single-chain variable fragment. These results indicate that C16:0-ceramide may be implicated in the vascular injury associated with COVID-19.

Cell-Specific Mechanisms in the Heart of COVID-19 Patients.

From the onset of the pandemic, evidence of cardiac involvement in acute COVID-19 abounded. Cardiac presentations ranged from arrhythmias to ischemia, myopericarditis/myocarditis, ventricular dysfunction to acute heart failure, and even cardiogenic shock. Elevated serum cardiac troponin levels were prevalent among hospitalized patients with COVID-19; the higher the magnitude of troponin elevation, the greater the COVID-19 illness severity and in-hospital death risk. Whether these consequences were due to direct SARS-CoV-2 infection of cardiac cells or secondary to inflammatory responses steered early cardiac autopsy studies. SARS-CoV-2 was reportedly detected in endothelial cells, cardiac myocytes, and within the extracellular space. However, findings were inconsistent and different methodologies had their limitations. Initial autopsy reports suggested that SARS-CoV-2 myocarditis was common, setting off studies to find and phenotype inflammatory infiltrates in the heart. Nonetheless, subsequent studies rarely detected myocarditis. Microthrombi, cardiomyocyte necrosis, and inflammatory infiltrates without cardiomyocyte damage were much more common. In vitro and ex vivo experimental platforms have assessed the cellular tropism of SARS-CoV-2 and elucidated mechanisms of viral entry into and replication within cardiac cells. Data point to pericytes as the primary target of SARS-CoV-2 in the heart. Infection of pericytes can account for the observed pericyte and endothelial cell death, innate immune response, and immunothrombosis commonly observed in COVID-19 hearts. These processes are bidirectional and synergistic, rendering a definitive order of events elusive. Single-cell/nucleus analyses of COVID-19 myocardial tissue and isolated cardiac cells have provided granular data about the cellular composition and cell type-specific transcriptomic signatures of COVID-19 and microthrombi-positive COVID-19 hearts. Still, much remains unknown and more in vivo studies are needed. This review seeks to provide an overview of the current understanding of COVID-19 cardiac pathophysiology. Cell type-specific mechanisms and the studies that provided such insights will be highlighted. Given the unprecedented pace of COVID-19 research, more mechanistic details are sure to emerge since the writing of this review. Importantly, our current knowledge offers significant clues about the cardiac pathophysiology of long COVID-19, the increased postrecovery risk of cardiac events, and thus, the future landscape of cardiovascular disease.

Lung pericytes as mediators of inflammation.

Pericytes are microvascular mural cells that directly contact endothelial cells. They have long been recognized for their roles in vascular development and homeostasis, but more recently have been identified as key mediators of the host response to injury. In this context, pericytes possess a surprising degree of cellular plasticity, behaving dynamically when activated and potentially participating in a range of divergent host responses to injury. Although there has been much interest in the role of pericytes in fibrosis and tissue repair, their involvement in the initial inflammatory process has been understudied and is increasingly appreciated. Pericytes mediate inflammation through leukocyte trafficking and cytokine signaling, respond to pathogen-associated molecular patterns and tissue damage-associated molecular patterns, and may drive vascular inflammation during human SARS-CoV-2 infection. In this review, we highlight the inflammatory phenotype of activated pericytes during organ injury, with an emphasis on novel findings relevant to pulmonary pathophysiology.

Single cell meta-analysis of EndMT and EMT state in COVID-19.

COVID-19 prognoses suggests that a proportion of patients develop fibrosis, but there is no evidence to indicate whether patients have progression of mesenchymal transition (MT) in the lungs. The role of MT during the COVID-19 pandemic remains poorly understood. Using single-cell RNA sequencing, we profiled the transcriptomes of cells from the lungs of healthy individuals (n = 45), COVID-19 patients (n = 58), and idiopathic pulmonary fibrosis (IPF) patients (n = 64) human lungs to map the entire MT change. This analysis enabled us to map all high-resolution matrix-producing cells and identify distinct subpopulations of endothelial cells (ECs) and epithelial cells as the primary cellular sources of MT clusters during COVID-19. For the first time, we have identied early and late subgroups of endothelial mesenchymal transition (EndMT) and epithelial-mesenchymal transition (EMT) using analysis of public databases for single-cell sequencing. We assessed epithelial subgroups by age, smoking status, and gender, and the data suggest that the proportional changes in EMT in COVID-19 are statistically significant. Further enumeration of early and late EMT suggests a correlation between invasive genes and COVID-19. Finally, EndMT is upregulated in COVID-19 patients and enriched for more inflammatory cytokines. Further, by classifying EndMT as early or late stages, we found that early EndMT was positively correlated with entry factors but this was not true for late EndMT. Exploring the MT state of may help to mitigate the fibrosis impact of SARS-CoV-2 infection.

Oral lesions in patients with severe COVID-19 in the National Institute of Respiratory Diseases in Mexico: Case series

Introduction SARS-CoV-2 is a neurotropic, mucotropic, and sialotropic virus that can affect the salivary glands' function, taste sensations, smell, and oral mucosa integrity.1 The oral cavity is a perfect habitat for SARS-CoV-2 invasion due to the special affinity the virus has for cells with angiotensinconverting enzyme (ACE2) receptors, such as those from the respiratory tract, oral mucosa, tongue, and salivary glands. Aphthous lesions with necrosis and hemorrhagic crusts have been described to manifest more regularly in older adults with immunosuppression and severe COVID-19 infection;one hypothesis for the development of aphthous lesions and/or ulcers is given due to the ACE2 receptor and the SARS-CoV-2 interaction, which could alter the epithelial lining of salivary glands and keratinocytes, causing lesions in the oral cavity.4 At the same time, different etiological factors such as infections, immune system alterations, and direct trauma to the oral mucosa or epithelium,5 may be related to the stress of a prolonged hospital stay.6 Including pressure in the oral cavity conditioned by the prone position, malposition of the endotracheal tube (mainly in the corners of the lips),7 medication-related nutritional deficiencies8 such as lopinavir, and ritonavir, oseltamivir, hydroxychloroquine, among others.9-12 Thrombotic vasculopathy secondary to COVID-19 has also been described, induced by system mediators in the microvascular walls, which impairs endothelial cells, and activates coagulation factors13 and a possible hypersensitivity reaction of the mucosa to the presence of SARS-CoV-2 in the epithelium14,15;there is also the hypothesis that it could be associated with an exanthem pattern induced by the inflammatory action of the SARSCoV-2 virus,16 presented as increased levels of cytokines (including interleukin-1, tumor necrosis facto-a), and arachidonic acid metabolites (prostaglandins) secondary to the stem cell factor production and the basic fibroblast growth factor of keratinocytes from the basal layer, in relation to post-inflammatory pigmentations that could appear in areas previously affected by trauma or chronic inflammation.17 Oral manifestations in COVID-19 patients appear, on many occasions, even before respiratory symptoms, although exanthematic lesions observed in COVID-19 patients can also be observed in other viral processes. Physical examination revealed a patient in a supine position with orotracheal intubation and orogastric tube, with aphthous-type ulcers, some of them had blood crusts of different sizes on the lower lip (both skin and mucosa), dorsum, and lateral edge of the tongue, gum, and vestibular fornix (Figure 3). Initial physical examination shows the patient in a supine position supported by high-flow nasal prongs, upper and lower lips edema and ulcer-like lesions with hematic crusts on both lips (Figure 4), topical management with steroids and GELCLAIRE® Oral Gel (glycyrrhetinic acid and polyvinylpyrrolidone) is observed.

Diosmetin alleviates acute lung injury caused by lipopolysaccharide by targeting barrier function.

Acute lung injury (ALI) is an acute and devastating disease caused by systemic inflammation e.g. patients infected with bacteria and viruses such as SARS-CoV-2 have an unacceptably high mortality rate. It has been well documented that endothelial cell damage and repair play a central role in the pathogenesis of ALI because of its barrier function. Nevertheless, the leading compounds that effectively accelerate endothelial cell repair and improve barrier dysfunction in ALI are largely unknown. In the present study, we found that diosmetin had promising characteristics to inhibit the inflammatory response and accelerate the repair of endothelial cells. Our results indicated that diosmetin accelerated wound healing and barrier repair by improving the expression of the barrier-related proteins, including zonula occludens-l (ZO-1) and occludin, in human umbilical vein endothelial cells (HUVECs) treated with lipopolysaccharide (LPS). Meanwhile, diosmetin administration significantly inhibited inflammatory response by decreasing the content of TNFα and IL-6 in the serum, alleviated lung injury by reducing lung wet/dry (W/D) ratio and histologic score, improved endothelial hyperpermeability by decreasing protein levels and neutrophil infiltration in the bronchoalveolar lavage fluid (BALF) and increasing ZO-1 and occludin expression in the lung tissues of LPS-treated mice. Mechanistically, diosmetin also mediated the expression of Rho A and ROCK1/2 in HUVECs treated with LPS, and fasudil, a Rho A inhibitor remarkably inhibited the role of diosmetin in ZO-1 and occludin proteins. All these findings of this study revealed that diosmetin can be an effective protector of lung injury and the Rho A/ROCK1/2 signal pathway plays a pivotal role in diosmetin accelerating barrier repair in ALI.

The Therapeutic Effects of EFNB2-Fc in a Cell Model of Kawasaki Disease.

The EphrinB2/EphB4 signaling pathway involves the regulation of vascular morphogenesis and angiogenesis. However, little is known about EphrinB2/EphB4 in the pathogenesis of Kawasaki disease (KD) and coronary artery aneurysm formation. Hence, this study aimed to explore the role of EphrinB2/EphB4 and the potential therapeutic effect of EphrinB2-Fc in the coronary arterial endothelial injury of KD. The levels of EphB4 were compared between KD patients and healthy children. Human coronary artery endothelial cells (HCAECs) were stimulated with sera from acute KD patients to establish the KD cell model. The overexpression of EphB4 or treatment with EphrinB2-Fc was found to intervene in the cell model. The cell migration, angiogenesis, and proliferation ability were assessed, and the expression of inflammation-related factors was measured. Our study showed that EphB4 showed low expression in both KD patients and the cell model of KD. The EphB4 protein levels in the CECs of CAA+ KD patients were much lower than those in healthy children. EphrinB2-Fc treatment of KD sera-activated HCAECs suppressed cell proliferation, reduced the expression of inflammation-related factors (such as IL-6 and P-selectin), and elevated cell angiogenesis ability. The results reveal that EphrinB2-Fc has a protective function in endothelial cells and has promising clinical applications for protecting vascular endothelium in patients with KD.

Gene silencing of endothelial von Willebrand factor reduces the susceptibility of human endothelial cells to SARS-CoV-2 infection.

Mechanisms underlying vascular endothelial susceptibility to infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are not fully understood. Emerging evidence indicates that patients lacking von Willebrand factor (vWF), an endothelial hallmark, are less severely affected by SARS-CoV-2 infection, yet the precise role of endothelial vWF in modulating coronavirus entry into endothelial cells is unknown. In the present study, we demonstrated that effective gene silencing by short interfering RNA (siRNA) for vWF expression in resting human umbilical vein endothelial cells (HUVECs) significantly reduced by 56% the cellular levels of SARS-CoV-2 genomic RNA. Similar reduction in intracellular SARS-CoV-2 genomic RNA levels was observed in non-activated HUVECs treated with siRNA targeting angiotensin-converting enzyme 2 (ACE2), the cellular gateway to coronavirus. By integrating quantitative information from real-time PCR and high-resolution confocal imaging, we demonstrated that ACE2 gene expression and its plasma membrane localization in HUVECs were both markedly reduced after treatment with siRNA anti-vWF or anti-ACE2. Conversely, siRNA anti-ACE2 did not reduce endothelial vWF gene expression and protein levels. Finally, SARS-CoV-2 infection of viable HUVECs was enhanced by overexpression of vWF, which increased ACE2 levels. Of note, we found a similar increase in interferon-ß mRNA levels following transfection with untargeted, anti-vWF or anti-ACE2 siRNA and pcDNA3.1-WT-VWF. We envision that siRNA targeting endothelial vWF will protect against productive endothelial infection by SARS-CoV-2 through downregulation of ACE2 expression and might serve as a novel tool to induce disease resistance by modulating the regulatory role of vWF on ACE2 expression.

COVID-19, Blood Lipid Changes, and Thrombosis.

Although there is increasing evidence that oxidative stress and inflammation induced by COVID-19 may contribute to increased risk and severity of thromboses, the underlying mechanism(s) remain to be understood. The purpose of this review is to highlight the role of blood lipids in association with thrombosis events observed in COVID-19 patients. Among different types of phospholipases A2 that target cell membrane phospholipids, there is increasing focus on the inflammatory secretory phospholipase A2 IIA (sPLA2-IIA), which is associated with the severity of COVID-19. Analysis indicates increased sPLA2-IIA levels together with eicosanoids in the sera of COVID patients. sPLA2 could metabolise phospholipids in platelets, erythrocytes, and endothelial cells to produce arachidonic acid (ARA) and lysophospholipids. Arachidonic acid in platelets is metabolised to prostaglandin H2 and thromboxane A2, known for their pro-coagulation and vasoconstrictive properties. Lysophospholipids, such as lysophosphatidylcholine, could be metabolised by autotaxin (ATX) and further converted to lysophosphatidic acid (LPA). Increased ATX has been found in the serum of patients with COVID-19, and LPA has recently been found to induce NETosis, a clotting mechanism triggered by the release of extracellular fibres from neutrophils and a key feature of the COVID-19 hypercoagulable state. PLA2 could also catalyse the formation of platelet activating factor (PAF) from membrane ether phospholipids. Many of the above lipid mediators are increased in the blood of patients with COVID-19. Together, findings from analyses of blood lipids in COVID-19 patients suggest an important role for metabolites of sPLA2-IIA in COVID-19-associated coagulopathy (CAC).

Pathological angiogenesis: mechanisms and therapeutic strategies.

In multicellular organisms, angiogenesis, the formation of new blood vessels from pre-existing ones, is an essential process for growth and development. Different mechanisms such as vasculogenesis, sprouting, intussusceptive, and coalescent angiogenesis, as well as vessel co-option, vasculogenic mimicry and lymphangiogenesis, underlie the formation of new vasculature. In many pathological conditions, such as cancer, atherosclerosis, arthritis, psoriasis, endometriosis, obesity and SARS-CoV-2(COVID-19), developmental angiogenic processes are recapitulated, but are often done so without the normal feedback mechanisms that regulate the ordinary spatial and temporal patterns of blood vessel formation. Thus, pathological angiogenesis presents new challenges yet new opportunities for the design of vascular-directed therapies. Here, we provide an overview of recent insights into blood vessel development and highlight novel therapeutic strategies that promote or inhibit the process of angiogenesis to stabilize, reverse, or even halt disease progression. In our review, we will also explore several additional aspects (the angiogenic switch, hypoxia, angiocrine signals, endothelial plasticity, vessel normalization, and endothelial cell anergy) that operate in parallel to canonical angiogenesis mechanisms and speculate how these processes may also be targeted with anti-angiogenic or vascular-directed therapies.

Diabetic endothelial microangiopathy and pulmonary dysfunction.

Type 2 diabetes mellitus (T2DM) is a widespread metabolic condition with a high global morbidity and mortality rate that affects the whole body. Their primary consequences are mostly caused by the macrovascular and microvascular bed degradation brought on by metabolic, hemodynamic, and inflammatory variables. However, research in recent years has expanded the target organ in T2DM to include the lung. Inflammatory lung diseases also impose a severe financial burden on global healthcare. T2DM has long been recognized as a significant comorbidity that influences the course of various respiratory disorders and their disease progress. The pathogenesis of the glycemic metabolic problem and endothelial microangiopathy of the respiratory disorders have garnered more attention lately, indicating that the two ailments have a shared history. This review aims to outline the connection between T2DM related endothelial cell dysfunction and concomitant respiratory diseases, including Coronavirus disease 2019 (COVID-19), asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF).

Local Complement Contributes to Pathogenic Activation of Lung Endothelial Cells in SARS-CoV-2 Infection.

Endothelial dysfunction and inflammation contribute to the vascular pathology of Coronavirus Disease 2019 (COVID-19). However, emerging evidence does not support direct infection of endothelial or other vascular wall cells and thus inflammation may be better explained as secondary responses to epithelial cell infection. In this study, we sought to determine whether lung endothelial or other resident vascular cells are susceptible to productive SARS-CoV-2 infection and how local complement activation contributes to endothelial dysfunction and inflammation in response to hypoxia and SARS-CoV-2 infected lung alveolar epithelial cells. We found that ACE2 and TMPRSS2 mRNA expression in lung vascular cells including primary human lung microvascular endothelial cells (HLMVEC), pericytes, smooth muscle cells and fibroblasts was 20-90-fold lower compared to primary human alveolar epithelial type II (AT2) cells. Consistently, we found that HLMVEC and other resident vascular cells were not susceptible to productive SARS-CoV-2 infection under either normoxic or hypoxic conditions. However, viral uptake without replication (abortive infection) was observed in HLMVEC when exposed to conditioned medium from SARS-CoV-2 infected human ACE2 stably transfected A549 epithelial cells (hACE2-A549). Furthermore, we demonstrated that exposure of HLMVEC to conditioned medium from SARS-CoV-2 infected hACE2-A549 cells and hypoxia resulted in upregulation of inflammatory factors such as ICAM1, VCAM1, IL-6 as well as complement components such as C3, C3AR1, C1QA and CFB. Taken together, our data support a model in which lung endothelial/vascular dysfunction during COVID-19 involves the activation of complement and inflammatory signaling and does not involve productive viral infection of endothelial cells. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

A Review on COVID-19: Primary Receptor, Endothelial Dysfunction, Related Comorbidities, and Therapeutics

Since December 2019, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused a global pandemic named coronavirus disease-19 (COVID-19) and resulted in a worldwide economic crisis. Utilizing the spike-like protein on its surface, the SARS-CoV-2 binds to the receptor angiotensin-converting enzyme 2 (ACE2), which highly expresses on the surface of many cell types. Given the crucial role of ACE2 in the renin–angiotensin system, its engagement by SARS-CoV-2 could potentially result in endothelial cell perturbation. This is supported by the observation that one of the most common consequences of COVID-19 infection is endothelial dysfunction and subsequent vascular damage. Furthermore, endothelial dysfunction is the shared denominator among previous comorbidities, including hypertension, kidney disease, cardiovascular diseases, etc., which are associated with an increased risk of severe disease and mortality in COVID-19 patients. Several vaccines and therapeutics have been developed and suggested for COVID-19 therapy. The present review summarizes the relationship between ACE2 and endothelial dysfunction and COVID-19, also reviews the most common comorbidities associated with COVID-19, and finally reviews several categories of potential therapies against COVID-19.