Ngele MP, Haubner B, Tanner FC, Ruschitzka F, Flammer AJ. An unresolved question. 2021;16:e0253524. 2021;1321:3343. Efficacy and tolerability of bevacizumab in patients with severe Covid-19. SARS-CoV-2 infection can also cause acute kidney injury (AKI). 2020;383:1208. This work was also supported by Program for Innovative Research Team of The First Affiliated Hospital of USTC (CXGG02), Anhui Provincial Key Research and Development Program (Grant No. Oliveira MR, Back GD, da Luz Goulart C, Domingos BC, Arena R, Borghi-Silva A. Endothelial function provides early prognostic information in patients with COVID-19: A cohort study. (i) COVID-19 directly affects sustentacular (SUS) cells through interactions with the ACE2 receptor, thereby leading to abnormal transmission of odor molecules. Li M, Zhu H, Liu Y, Lu Y, Sun M, Zhang Y, et al. Schimmel L, Chew KY, Stocks CJ, Yordanov TE, Essebier P, Kulasinghe A, et al. S protein treatment of HAECs leads to increased secretion of inflammatory molecules (IL-6, MCP-1 and IL-18) and PAI-1, which can be attenuated by minerocorticoid receptor antagonists [56]. As well, nAChR activators through interaction with diverse signaling pathways can reduce the risk of inflammatory disorders in COVID-19. J Med Virol. Also, CD209L/L-SIGN was identified as another receptor for mediating SARS-CoV-2 entry into human cells which can also interacts with ACE2 to facilitate SARS-CoV-2 entry [21]. PLoS One. SARS-CoV-2 infection relies on ACE2 expression in ECs [48]. Based on the important role of endothelial dysfunction in COVID-19, several categories of endothelial protective drugs are possible to ameliorate endothelial dysfunction in COVID-19. A recent study has shown that SARS-CoV-2-infection of human brain microvascular ECs showed augmented caspase 3 cleavage and apoptotic cell death of endothelial cells. Cell Metab. It is initially conceived that ACE inhibitors (ACEIs) or Ang-II receptor blockers (ARBs), two widely-used anti-hypertensive drugs targeting the renin-angiotensin system (RAS), could increase the vulnerability to SARS-CoV-2 by upregulating the expression of ACE-2. Keywords: Cardiovasc Res. Wenzel J, Lampe J, Mller-Fielitz H, Schuster R, Zille M, Mller K, et al. Both SARS-CoV and SARS-CoV-2 utilizes ACE2 and membrane-bound co-factors for virus entry. 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. Zhang L, Zhou L, Bao L, Liu J, Zhu H, Lv Q, et al. Further identification of alternative receptors for SARS-CoV-2 is warranted [51]. SARS-CoV-2 crosses the blood-brain barrier accompanied with basement membrane disruption without tight junctions alteration. SARS-CoV-2 infection is associated with reduced krppel-like factor 2 in human lung autopsy. Liu Y, Zhang HG. Mitochondrial dysfunction usually occurs after viral infection, thereby exacerbating tissue damage. Abraham GR, Kuc RE, Althage M, Greasley PJ, Ambery P, Maguire JJ, et al. 5. Kang S, Tanaka T, Inoue H, Ono C, Hashimoto S, Kioi Y, et al. In COVID-19 patients, heart failure and myocardial injury are frequent complications, underscoring the clinical utility of SGLT2 inhibitors [128]. Increased glycocalyx components (after damage or destruction) were observed in COVID-19 patients compared with control subjects. Unauthorized use of these marks is strictly prohibited. 2022;13:830061. After virus infection, ensuing cytokine storm occurs in severe COVID-19 patients, particularly the elevated secretion of pro-inflammatory cytokine interleukin 6 (IL-6). Endothelial damage in acute respiratory distress syndrome. Cytokine storm in COVID-19 can trigger inflammation via the JAK/STAT pathway, which results in increased recruitment of leukocytes/immune cells [146]. Front Physiol. Kang X, Jin D, Jiang L, Zhang Y, Zhang Y, An X, et al. The following is a summary of "Optimal positive end-expiratory pressure reduces right ventricular dysfunction in COVID-19 patients on venovenous extracorporeal membrane oxygenation: A retrospective single-center study," published in the February 2023 issue of Critical Care by Estoos et al. Biochimica et Biophysica Acta Mol Basis Dis. Heterogeneous ACE2 expression and endothelial damage was observed in COVID-19 autopsy tissues. 2021;8:648290. Crit Care (Lond, Engl). COVID-19-Associated lung microvascular endotheliopathy: a from the bench perspective. Clipboard, Search History, and several other advanced features are temporarily unavailable. It can be complicated by arrhythmias or thromboembolic episodes. COVID-19 and thermoregulation-related problems: Practical Statins are prescribed as the first-choice treatment for patients with hypercholesterolemia and coronary artery disease due to their lipid-lowering and pleiotropic anti-inflammatory, antioxidant, anti-thrombotic and immune-modulatory effects. It remains to be investigated further whether TCM ameliorates COVID-19 partially by improving endothelial function. Molecular underpinnings of metabolic alterations caused by SARS-CoV-2 infection warrants further studies; Lastly, considering the evolving mutations of SARS-CoV-2 (such as Delta variant and Omicron variant), effect and mechanism of these variants in viral entry and endothelial functionality warrant further studies. In light of the important contribution of endothelial dysfunction to COVID-19 and its sequelae, we overviewed, in this article, the pivotal role and mechanistic basis of endothelial dysfunction in COVID-19 and its multi-organ complications and markers of endothelial activation. COVID-19 and Respiratory System Disorders | Arteriosclerosis J Mol Cell Cardiol. Potential mechanisms of coronavirus disease 2019 (COVID-19)-induced olfactory dysfunction. Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection represents an ongoing public health burden leading to extensive morbidity and mortality worldwide [1]. 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. Study implicates diaphragm dysfunction as a potential cause for Pang J, Xu F, Aondio G, Li Y, Fumagalli A, Lu M, et al. Cytokine storm and histopathological findings in 60 cases of COVID-19-related death: from viral load research to immunohistochemical quantification of major players IL-1, IL-6, IL-15 and TNF-. The Burden of Cognitive Dysfunction in COVID-19 Front Med. Nature. 2021;93:2506. A recent study has shown the possible involvement of EndoMT in COVID-19. Hyperpyrexia is an elevation of body temperature above 106.7F (41.5C) due to an abnormally increased hypothalamic-thermoregulatory set. An analysis of patients with a chief complaint of difficulty moving. Signal Transduct Target Ther. Dexamethasone treated group exhibited a significantly decreased levels of various markers associated with endothelial dysfunction, including Ang-2, ICAM-1, and sRAGE [135]. Curative anticoagulation prevents endothelial lesion in COVID-19 patients. Atypical presentation of Covid-19 in persons with spinal cord injury Cytokine storm. 1). 2021;41:176073. 2021;39:8201. "Persisting pulmonary dysfunction in pediatric post-acute Covid-19" "Our study demonstrates widespread functional lung alterations are present in children and adolescents." 30 Apr 2023 18:49:04 In addition, reduced flow-mediated dilation (FMD, an easily obtainable method to assess endothelial dysfunction) was observed in COVID-19 patients, thus offering additional markers to serve as the proxy of endothelial cell activation [108]. Heparanase is a putative mediator of endothelial glycocalyx damage in COVID-19 - A proof-of-concept study. Schulthei C, Willscher E, Paschold L, Gottschick C, Klee B, Henkes SS, et al. Lee S, Yu Y, Trimpert J, Benthani F, Mairhofer M, Richter-Pechanska P, et al. JAMA Netw Open. All these reported effects could justify the curative effects of tocilizumab on COVID-19 [138]. 2021. https://doi.org/10.1093/qjmed/hcab252. Int J Infect Dis. A systematic review was conducted by searching MEDLINE, EMBASE, and the preprint server MedRxiv from their inception until May 11, 2020, using the terms anosmia or hyposmia or dysosmia or olfactory dysfunction or olfaction disorder or smell dysfunction or ageusia or hypogeusia or dysgeusia or taste dysfunction or gustatory dysfunction or neurological and COVID-19 or 2019 novel coronavirus or . Recently, miR-98-5p was identified as a negative regulator of TMPRSS2 gene transcription in human lung and umbilical vein ECs [98]. Mechanistically, fluvoxamine is a sigma-1 receptor (S1R) agonist which, on the one hand, reduces the expression of IL-6, while increasing that of eNOS. 2022. https://doi.org/10.21203/rs.3.rs-1762855/v1. However, compromised glycocalyx integrity promotes S protein/ACE2 interaction and facilitates viral entry [68]. Vigilance on new-onset atherosclerosis following SARS-CoV-2 infection. Non-coding RNA. Would you like email updates of new search results? Mezoh G, Crowther NJ. Eur J Clin Invest. Oskotsky T, Maric I, Tang A, Oskotsky B, Wong RJ, Aghaeepour N, et al. Medications to protect and/or restore the endothelial glycocalyx integrity hold great therapeutic potential for COVID-19 associated glycocalyx disruption. Therefore, the therapeutic role of JIVC in treating severe COVID-19 patients warrants further investigation [160]. 2021;19:5. 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. COVID-19 and erectile dysfunction: endothelial dysfunction and beyond. Chen L, Li X, Chen M, Feng Y, Xiong C. The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. 2020;7:559811. Thrombosis J. An official website of the United States government. Tissue Barriers. Barbosa LC, Gonalves TL, de Araujo LP, Rosario LVO, Ferrer VP. The levels of biomarkers of endothelial cell activation/injury well correlate with the expression level of pro-inflammatory cytokines and chemokines [103]. 3). Validated psychophysical testing revealed hyposmia in 18% and hypogeusia in even 32% of 303 included patients. Kaundal RK, Kalvala AK, Kumar A. Front Med. Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial. Like other types of organ injury, SARS-CoV-2 infection causes AKI by both direct and indirect mechanisms, including endotheliitis, thrombosis and glucolipid derangement. While COVID-19 primarily affects the lungs, it also affects other organs, the heart in particular. Tocilizumab improves oxidative stress and endothelial glycocalyx: A mechanism that may explain the effects of biological treatment on COVID-19. 2023 Mar 31;102(13):e33345. In addition, plasma profiling study of patients with COVID-19 revealed elevated circulating levels of markers of angiogenesis (such as VEGF-A) in COVID-19 patients [84]. 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. Vassiliou AG, Kotanidou A, Dimopoulou I, Orfanos SE. Endothelial junctions (EJ) are crucial to maintain EC integrity and normal microvascular functions due to the adhesive properties of Vascular endothelial (VE)-cadherin to glue EC together. Cecon E, Fernandois D, Renault N, Coelho CFF, Wenzel J, Bedart C, et al. The most common clinical presentation of severe COVID-19 is acute respiratory failure consistent with the acute respiratory distress syndrome. Eur J Intern Med. Ebihara T, Matsumoto H, Matsubara T, Togami Y, Nakao S, Matsuura H, et al. Muramatsu K, Nagasawa H, Takeuchi I, Jitsuiki K, Ohsaka H, Ishikawa K, Yanagawa Y. J Rural Med. Sulodexide significantly improves endothelial dysfunction and alleviates chest pain and palpitations in patients with long-COVID-19: Insights From TUN-EndCOV study. Endothelial contribution to COVID-19: an update on mechanisms and therapeutic implications. Clin Transl Immunol. J Virol. Interleukin-1RA mitigates SARS-CoV-2-induced inflammatory lung vascular leakage and mortality in humanized K18-hACE-2 mice. 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. Direct or indirect mechanisms are operating to collectively indicate the alterations in vascular homeostasis in COVID-19 [54]. Anakinra for severe forms of COVID-19: a cohort study. CD209L/L-SIGN and CD209/DC-SIGN act as receptors for SARS-CoV-2. 2020;41:303844. Kondo Y, Larabee JL, Gao L, Shi H, Shao B, Hoover CM, et al. Furthermore, it has been demonstrated that exosomes from severe COVID-19 patients trigger the activation of caspase-1 and NLRP3 inflammasome and release of IL-1 in ECs [64]. 2021;289:68899. Rotoli BM, Barilli A, Visigalli R, Ferrari F, DallAsta V. Endothelial cell activation by SARS-CoV-2 Spike S1 protein: a crosstalk between endothelium and innate immune cells. In addition, S1 subunit of SARS-CoV-2 spike protein (S1) decreased endothelial barrier function in cultured human pulmonary microvascular ECs [22]. Endothelial dysfunction in COVID-19: a unifying mechanism and a potential therapeutic target. Liu Z, Ma X, Ilyas I, Zheng X, Luo S, Little PJ, et al. 2017BT01S131), Hefei Comprehensive National Science Center (Grant No. 2021;11:807691. BMJ. Corrao S, Pinelli K, Vacca M, Raspanti M, Argano C. Type 2 diabetes mellitus and COVID-19: a narrative review. Potje SR, Costa TJ, Fraga-Silva TFC, Martins RB, Benatti MN, Almado CEL, et al. Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, 230001, China, You can also search for this author in In a single-center observational study, 82% of critically ill COVID-19 patients have significantly lower plasma level of vitamin C [154]. Pathogenesis and Transmission of COVID-19. Elevated expression of serum endothelial cell adhesion molecules in COVID-19 patients. 2022;9:866113. 2022;185:49312. Aye YN, Mai AS, Zhang A, Lim OZH, Lin N, Ng CH, et al. Single-cell transcriptomic atlas of primate cardiopulmonary aging. Mortality of COVID-19 patients is increased by comorbidities of cardiovascular disease and hypertension in particular. In addition, due to the fact that trained immunity in ECs is an important mechanism in propagating endothelial response to inflammatory/immune insults after prior exposure to microbial stimuli [100], detailed mechanisms of epigenetic memory in transducing the SARS-COV-2 infection-induced immune signal needs further studies. Hu B, Huang S, Yin L. The cytokine storm and COVID-19. It has been reported that injury to the endothelial glycocalyx and the release of syndecan-1 (SDC-1) was observed in severe COVID-19 patients [69, 70]. SARS-CoV-2 spike promotes inflammation and apoptosis through autophagy by ROS-suppressed PI3K/AKT/mTOR signaling. The pleiotropic effects of metformin help to control hyperglycemia, inhibit viral entry, and reduce inflammation following SARS-CoV-2 infection. Results of the first interim analysis. Endothelial immunity trained by coronavirus infections, DAMP stimulations and regulated by anti-oxidant NRF2 may contribute to inflammations, myelopoiesis, COVID-19 cytokine storms and thromboembolism. 2022; 2090792. https://doi.org/10.1080/21688370.2022.2090792. Lancet (Lond, Engl). Acute brain dysfunction is highly prevalent in COVID-19 patients. Pawlos A, Niedzielski M, Gorzelak-Pabi P, Broncel M, Woniak E. COVID-19: direct and indirect mechanisms of statins. 2020;222:178993. Thank you for visiting nature.com. Thermoregulation and afterdrop during hypothermia in patients with poikilothermia. The spatio-temporal release of VEGF-A and its effects on endothelial proliferation, migration and capillary-like tube formation warrant further study. 2020;202:117881. Effects of Shuanghuanglian oral liquids on patients with COVID-19: a randomized, open-label, parallel-controlled, multicenter clinical trial. Fang W, Jiang J, Su L, Shu T, Liu H, Lai S, et al. Many patients with severe COVID-19 present with coagulation abnormalities that mimic other systemic coagulopathies associated with severe infections, such as disseminated intravascular coagulation (DIC) or thrombotic microangiopathy, but COVID-19 has distinct features. PLoS One. One of the most peculiar characteristics of the olfactory dysfunction in COVID-19 is that it typically starts very abruptly, lasts for only a few days (mean or median ranges: 7-21.6 days [34,35]), and smell can recover just as abruptly as it was lost. Potential value of circulating endothelial cells for the diagnosis and treatment of COVID-19. 2012;36:5715. Intriguingly, the main coronary arteries have no detectable expression of ACE2, suggesting the occurrence of COVID-19-induced endotheliitis in small vessel like capillaries; however, the culprit in the main coronaries are largely dependent on indirect mechanism arising from SARS-CoV-2 infection [47]. However, COVID-19 serum induced glycocalyx destruction was reversed by a non-anticoagulant heparin fragment [113]. The following is a summary of "Optimal positive end-expiratory pressure reduces right ventricular dysfunction in COVID-19 patients on venovenous extracorporeal membrane oxygenation: A retrospective single-center study," published in the February 2023 issue of Critical Care by Estoos et al. Kim WY, Kweon OJ, Cha MJ, Baek MS, Choi SH. 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]. Thermoregulatory dysfunction energy subsidy | energy.gov.au 2021;65:2226. 2022;43:36776. 2022;36:e22052. eCollection 2023 Apr. Management requires the immediate reduction of core temperature. Moretta P, Maniscalco M, Papa A, Lanzillo A, Trojano L, Ambrosino P. Cognitive impairment and endothelial dysfunction in convalescent COVID-19 patients undergoing rehabilitation. Google Scholar. 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. Article CAS Since the outbreak of COVID-19 in early 2020, emerging evidence has demonstrated endothelial dysfunction as the unifying and central mechanism of COVID-19 [6]. 2020;18:23919. Circulation. Here, we reviewed the potential mechanism of endothelial activation in COVID-19 by overviewing the most recent literature, with the aim to provide targeted therapies (Fig. 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 addition, nAChR activators may . Resistin is peptide hormone derived from adipose tissue which is associated with endothelial injury and inflammatory response. Fodor A, Tiperciuc B, Login C, Orasan OH, Lazar AL, Buchman C, et al. Microcirculation (N. Y, N. Y: 1994). Ambrosino P, Calcaterra IL, Mosella M, Formisano R, DAnna SE, Bachetti T, et al. Ice water immersion has been shown to be superior to alternative cooling measures. Circulating level of Angiopoietin-2 is associated with acute kidney injury in coronavirus disease 2019 (COVID-19). Gladka MM, Maack C. The endothelium as Achilles heel in COVID-19 patients. The disrupted glycocalyx structure leads to hyperinflammatory response and oxidative stress, which leads to increased susceptibility to SARS-CoV-2 infection [67]. and JavaScript. The therapeutic potential of senolytics in COVID-19 patients warrants studies from clinical trials. The existence of cytokine storm could trigger vascular leakage, endothelial permeability in particular. 2021;321:L477l84. Recent studies have suggested that LSEC dysfunction is involved in COVID-19 associated liver injury [34]. The net effect of SARS-COV-2 infection induced senescence and angiogenesis is potentially dependent on stage of disease. Pharmacol Rev. Syndecan-1, an important vascular component of glycocalyx released after vasculitis and injury, well correlates with the marker of coagulation (D-dimer) in particular. Erectile Dysfunction Drugs Market Market Projection and - MarketWatch QJM. Front Cardiovasc Med. Nogueira RC, Minnion M, Clark AD, Dyson A, Tanus-Santos JE, Feelisch M. On the origin of nitrosylated hemoglobin in COVID-19: Endothelial NO capture or redox conversion of nitrite? 2021;13:2090614. Evaluation of endothelial dysfunction in COVID-19 with flow-mediated dilatation. Cell Rep Med. Respir Med. 2022 Dec 23;11(4):1728-1735. doi: 10.1002/fsn3.3202. 2021;10:186. Eur Heart J. Endothelial dysfunction in COVID-19: Current findings and therapeutic implications. Besides directly infected by SARS-CoV-2, the ECs also undergo injury by systemic inflammation caused by over-activation of innate immune response, referring to cytokine storm [91, 92]. Excessive production of mtROS causes oxidative stress that perpetuates ECs inflammation, senescence and dysfunction. Noris M, Benigni A, Remuzzi G. The case of complement activation in COVID-19 multiorgan impact. COVID-19 is associated with several common symptoms in the acute phase that can linger during recovery. 2021;2021:8671713. Ikonomidis I, Pavlidis G, Katsimbri P, Lambadiari V, Parissis J, Andreadou I, et al. Basta G. Direct or indirect endothelial damage? Evidently, based on the cytokine storm in severe or critically ill COVID-19 patients, targeted inhibition of pro-inflammatory cytokines, such as IL-1, IL-6 and downstream signal transduction pathways appears to be important avenues [93]. Several clinical trials are ongoing to evaluate the safety and efficacy of JAK/STAT inhibitors [146]. 2022;167:926. From a study cohort (consisting of 76% male and 24% female individuals), there was at least one abnormality of diaphragm muscle function on structure visualized by ultrasound in 80% of cases. 2020;126:167181. 2020;2:e393e400. 2019;117:1522. This study provides additional clinical evidence supporting continuation of metformin use in COVID-19 patients with pre-existing T2DM by paying close attention to kidney function and acidosis [126]. 2022: 1-10. Blood. 2021;34:812. TCM could significantly relieve clinical symptoms, reduce disease severity, reduce the need for mechanical ventilation, shortening the duration of hospitalization, accelerate symptom recovery, and ultimately reduce mortality rate [161,162,163,164]. SARS-CoV-2 or viral proteins can infect endothelial cells and other host cells via reported receptors and the vicious cycle was perpetuated. SARS-CoV-2 spike protein S1-mediated endothelial injury and pro-inflammatory state is amplified by dihydrotestosterone and prevented by mineralocorticoid antagonism. 2021;290:43743. Cardiovasc Res. Pulm Circ. PubMed Central 2020;116:1097100. Nutrients. For example, one study reported that primary human ECs express minimal level of ACE2 and the protease TMPRSS2, which limits their ability to generate highly infectious viral particles [50]. Endothelial integrity is essential for maintaining the pulmonary capillary-alveolar barrier and lung homoeostasis. 4 and 5) [101]. Yuen KS, Ye ZW, Fung SY, Chan CP, Jin DY. DAgnillo F, Walters KA, Xiao Y, Sheng ZM, Scherler K, Park J, et al. XDB38010100). 2022;11:1972. In addition, mtDNA release also increased vascular reactivity to ET1[94]. In this regard, miR-24-3p has recently been identified as an essential regulator of Neuropilin-1 gene transcription, thereby maintaining barrier integrity via suppressing VEGF-induced endothelial leakage in human brain ECs [99]. Xu, Sw., Ilyas, I. 2021;24:4036. Collectively, based on the multifaceted nature of endothelial dysfunction and complex patho-mechanisms of COVID-19, it warrants to be evaluated whether directly targeting endothelial dysfunction could result in a clinically significant improvement in outcome of COVID-19 patients. Nat Med. 2022;115:7783. 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]. Dexamethasone may improve severe COVID-19 via ameliorating endothelial injury and inflammation: A preliminary pilot study. The effect of glucocorticoids on COVID-19 might be multifactorial, and their endothelium-stabilizing properties by direct activation of endothelial glucocorticoid receptors to block production of IL-6 and VEGF might be the main operating mechanisms [19].
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