2022;21:e13646. Kang S, Tanaka T, Inoue H, Ono C, Hashimoto S, Kioi Y, et al. 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]. government site. Cells. 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]. CAS Int J Infect Dis. NO also has an anti-thrombotic action, by preventing leukocyte and platelet adhesion to activated endothelium, thereby inhibiting immunothrombosis and atherosclerotic plaque development [15]. 2021;9:1220. 2022;25:22540. 01 May 2023 01:18:34 More recently, it is reported that thrombomodulin level was associated with augmented infiltration of immune cells in autopsy lung tissues [79], explaining the existence of thromboembolism in COVID-19 patients. Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial. It is reported that COVID-19-patients had higher number of CECs than COVID-19-free subjects. FOIA 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]. Cell Metab. Hyperthermia, defined as a core temperature of >40.5C, may present with sweating, flushing, tachycardia, fatigue, lightheadedness, headache, and paresthesia, progressing to weakness, muscle cramps, oliguria, nausea, agitation, hypotension, syncope, confusion, delirium, seizures, and coma. This dual-function mechanisms suggest the important role of L-SIGN as the molecular bridge between ACE2 and SARS-CoV-2 spike protein to allow for virus infection in the patients. Henry BM, de Oliveira MHS, Cheruiyot I, Benoit JL, Cooper DS, Lippi G, et al. Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. Thus, COVID-19 is deemed as a (micro)vascular and endothelial disease. 2020;32:17687. Article 2021;348:109657. MeSH Thrombosis Res. 2021;107:2323. Impact of sodium glucose cotransporter 2 (SGLT2) inhibitors on atherosclerosis: from pharmacology to pre-clinical and clinical therapeutics. 2022;13:868679. 2021;24:4036. However, there are also reports showing that ACE2 expression is absent from human ECs. It can be complicated by arrhythmias or thromboembolic episodes. All the above evidence pinpoints the protective effect of heparin in COVID-19 could largely be attributable to glycocalyx-stabilizing effect. Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, et al. Efficacy and tolerability of bevacizumab in patients with severe Covid-19. Zheng H, Cheng J, Ho HC, Zhu B, Ding Z, Du W, Wang X, Yu Y, Fei J, Xu Z, Zhou J, Yang J. Six I, Guillaume N, Jacob V, Mentaverri R, Kamel S, Boullier A, et al. Barbosa LC, Gonalves TL, de Araujo LP, Rosario LVO, Ferrer VP. HHS Vulnerability Disclosure, Help The year in cardiovascular medicine 2021: heart failure and cardiomyopathies. Senolytic drugs such as navitoclax and quercetin/dasatinib combination selectively eradicated senescent cells and reduced inflammation in SARS-CoV-2-infected animals [89]. 2021;276:119376. du Preez HN, Aldous C, Hayden MR, Kruger HG, Lin J. Pathogenesis of COVID-19 described through the lens of an undersulfated and degraded epithelial and endothelial glycocalyx. SARS-CoV-2 or viral proteins can infect endothelial cells and other host cells via reported receptors and the vicious cycle was perpetuated. Chang R, Mamun A, Dominic A, Le NT. 2022;17:30. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. These studies illustrated that TCM in combination with standard care might be safe and potentially effective for COVID-19. However, the pathophysiology of acute and post-acute manifestations of COVID-19 (long COVID-19) is understudied. Food Sci Nutr. ACE2 can also undergo shedding and the soluble form of ACE2 (sACE2) can be released into circulating blood. The combination of multiple markers could afford better discriminative ability for diagnosis of coagulopathy and thromboembolism and are predictive of ICU admission in COVID-19 patients. Effect of SARS-CoV-2 proteins on vascular permeability. Pathogenesis and Transmission of COVID-19. An analysis of patients with a chief complaint of difficulty moving. 2208085J08) and Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (Grant No. Eur Heart J. Cardiovasc Res. PMC 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. Internet Explorer). EndoMT can be induced by cytokine mixture in cultured endothelial cells, for example, the combination of TNF- and IL-1, IL-1 and TGF1, etc. 2021;11:807691. 2021;93:2506. The clinical detection of thermoregulatory impairment provides important diagnostic and localizing information in the evaluation of disorders that impair thermoregulatory pathways, including autonomic neuropathies and ganglionopathies. CAS Mol Med (Camb, Mass). SARS-CoV-2 Spike triggers barrier dysfunction and vascular leak via integrins and TGF- signaling. Employing mechanical ventilation techniques on venovenous extracorporeal membrane oxygenation (VV ECMO . J Hepatol. 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]. 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. Endothelial dysfunction in COVID-19: a unifying mechanism and a potential therapeutic target. Atherosclerosis. J Med Virol. 2022;185:49312. An important question in endothelial dysfunction caused by SARS-Co-V2 is whether SARS-CoV-2 can infect and cause (passively or actively) endothelial dysfunction and long COVID [7]. Slider with three articles shown per slide. ACE2 is described as the first identified receptor responsible for the entry for SARS-CoV-2 into host cells including ECs [46]. 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 krppel-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. 2021;16:e0254167. Huang Q, Wu X, Zheng X, Luo S, Xu S, Weng J. Thermoregulatory dysfunction is defined as significant loss of a person's capacity to control body temperature, and is associated with medical conditions that result in the person's health and bodily function being seriously affected when exposed to extremes of environmental temperatures. ISSN 1745-7254 (online) COVID-19 is associated with several common symptoms in the acute phase that can linger during recovery. Huet T, Beaussier H, Voisin O, Jouveshomme S, Dauriat G, Lazareth I, et al. Plasma from COVID-19 patients triggered glycocalyx shedding and disruption in endothelial cells, which can be prevented after treatment with heparin [66]. Glycocalyx protein component can be degraded by degrading enzyme such as heparinase. Google Scholar. 2021;178:38648. Biomedicines. Google Scholar. 2022: e0095122. However, several JAK/STAT inhibitors such as ruxolitinib, tofacitinib and baricitinib can suppress cytokine signaling cascade. Endothelial damage in acute respiratory distress syndrome. This leads to decreased expression of VE-cadherin in lung endothelial cells. 2020;142:160911. Pharmacol Res. Ding Y, Zhou Y, Ling P, Feng X, Luo S, Zheng X, et al. Endothelial contribution to COVID-19: an update on mechanisms and therapeutic implications. Glycocalyx layer regulates vascular barrier integrity, leukocyte adhesion, mechanosensing, mechanotransduction, anti-inflammatory and anti-thrombotic functions [109]. Epub 2023 Jan 6. Although current pharmacotherapies against acute and post-acute COVID-19 mainly centered on blocking viral replication and limiting inflammation/inflammasome activation, it is likely that novel therapeutic approaches targeting endothelial dysfunction could represent a promising strategy to cardiovascular sequelae in COVID-19 convalescent patients [6] in light of elevated circulating level of biomarker soluble P-selectin in COVID-19 convalescent donors compared to healthy controls [175]. 2. Evaluation of endothelial dysfunction in COVID-19 with flow-mediated dilatation. Protein Cell. Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, et al. Fardman A, Zahger D, Orvin K, Oren D, Kofman N, Mohsen J, et al. Dexamethasone in hospitalized patients with Covid-19. Possible involvement of Syndecan-1 in the state of COVID-19 related to endothelial injury. In addition to the above drugs discussed, there are several other reports showing that serine protease inhibitors (camostat mesylate), KLF2 activators [120], RIPK3 inhibitors [166], spironolactone [77], glycocalyx repairing drugs [67], purified glycosaminoglycan mixture sulodexide [167], CCR5 blockers (Maraviroc), anti-VEGF (bevacizumab [168]), adrecizumab [169], mesenchymal stem cell therapy [170], estrogen [171], melatonin [172] and NO donor [173] could also be beneficial (Fig. COVID-19 is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a novel -coronavirus infecting human cells of the respiratory tract, vascular endothelium, heart, gut, and immune system [].The virus binds the angiotensin-converting enzyme 2 (ACE2) receptor, highly expressed on the target host cells, through a spike (S) protein . Resistin associated with cytokines and endothelial cell adhesion molecules is related to worse outcome in COVID-19. 2022. https://doi.org/10.1164/rccm.202207-1258ED. Cytokine storm. 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. SARS-CoV-2 infection is associated with reduced krppel-like factor 2 in human lung autopsy. In these cardiovascular complications, endothelial dysfunction plays a fundamental role [27]. These findings agree with a recent retrospective analysis by Zhang et al. Circulation. Cheng X, Liu YM, Li H, Zhang X, Lei F, Qin JJ, et al. 2022;9:826218. QJM. Acute brain dysfunction is highly prevalent in COVID-19 patients. Schnaubelt S, Oppenauer J, Tihanyi D, Mueller M, Maldonado-Gonzalez E, Zejnilovic S, et al. 1996 Oct-Nov;82(10-11):108-14. Therefore, IL-6 trans-signaling represents the mechanistic link between the coagulopathy/endotheliopathy and COVID-19 associated liver injury [35]. Shao Y, Saredy J, Xu K, Sun Y, Saaoud F, Drummer CT, et al. sharing sensitive information, make sure youre on a federal Okada H, Yoshida S, Hara A, Ogura S, Tomita H. Vascular endothelial injury exacerbates coronavirus disease 2019: The role of endothelial glycocalyx protection. Kondo Y, Larabee JL, Gao L, Shi H, Shao B, Hoover CM, et al. Similar effects were observed in ECs infected with SARS-CoV-2 spike pseudovirions (SCV-2-S) [55]. Human lung microvascular endothelial cells (HLMVEC) are activated after infection with the S1 protein or S1 infected human macrophages, evidenced by increased expression of pro-coagulant marker (tissue factor), and cytokines/chemokines (ICAM-1, VCAM-1 and MCP1) [54]. N Engl J Med. 2020;9:1652. Role of traditional chinese medicine in treating severe or critical covid-19: a systematic review of randomized controlled trials and observational studies. The intact barrier structure of sulfated glycocalyx of the endothelium could repel SARS-CoV-2. 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. Xiong S, Zhang L, Richner JM, Class J, Rehman J, Malik AB. Front Immunol. It is reported that under normal conditions, pulmonary ECs express minimal level of ACE2. Forensic Sci Med Pathol. Zhang XJ, Qin JJ, Cheng X, Shen L, Zhao YC, Yuan Y, et al. Of . Emerging evidence has suggested that thinning of endothelial glycocalyx layer is associated with COVID-19, and thus the glycocalyx integrity was perceived as an important therapeutic target in COVID-19 [109, 110]. SARS-CoV-2 spike protein impairs endothelial function via downregulation of ACE 2. The authors observed elevated levels of markers of coagulopathy/endotheliopathy and liver injury (ALT) in COVID-19 patients. Semin Vasc Surg. volume44,pages 695709 (2023)Cite this article. 2020;222:8948. COVID-19-related neuropathology and microglial activation in elderly with and without dementia. Consistent with this notion, elevated level of C3a in severe COVID-19 patients induced the activation of CD16+ cytotoxic T cells which promotes endothelial injury and the release of monocyte chemoattractant proteins as well as neutrophil activation [96]. Stahl K, Brsen JH, Hoeper MM, David S. Direct evidence of SARS-CoV-2 in gut endothelium. Top manufacturers . Samuel SM, Varghese E, Bsselberg D. Therapeutic potential of metformin in COVID-19: reasoning for its protective role. COVID-19 is characterized by excessive production of inflammatory mediators (IL-1, IL-6, IL-8, TNF-, MCP-1, IP10, RANTES, G-CSF and M-CSF) in a small portion of severe cases due to the severe cytokine storm [60,61,62]. The burst of ROS after SARS-CoV-2 infection will elicit long-term deleterious effects on endothelial cells, including decreased eNOS expression and NO bioavailability as well as flow-mediated vasodilation in COVID-19 patients. 2021;384:693704. 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. Fiorentino G, Coppola A, Izzo R, Annunziata A, Bernardo M, Lombardi A, et al. ACE inhibitors, angiotensin receptor blockers and endothelial injury in COVID-19. ACE2 angiotensin-converting enzyme-2, ACEI angiotensin converting enzyme inhibitors, ARB angiotensin receptor blockers, BRD4i bromodomain-containing protein 4 inhibitors, JAK janus kinase, SGLT2i sodium-glucose cotransporter-2 inhibitors. 2020;56:2003167. SARS-CoV-2 infection of human brain microvascular endothelial cells leads to inflammatory activation through NF-B non-canonical pathway and mitochondrial remodeling. Please enable it to take advantage of the complete set of features! Handb Clin Neurol. Kang S, Kishimoto T. Interplay between interleukin-6 signaling and the vascular endothelium in cytokine storms. Biomolecules. However, statin use can also induce the expression of ACE2, which may potentially increase virus entry [117]. 2021;375:n2400. Overall, a plethora of biomarkers of endothelial cell activation and injury have been proposed and validated preclinically and in human patients, offering effective diagnostic tools for monitoring endothelial function in COVID-19. Inhibition of heparanase by a non-anticoagulant heparin fragment prevented glycocalyx destruction in response to COVID-19 serum treatment [113]. CAS PubMed Central Pathol Res Pract. Regeneration of glycocalyx by heparan sulfate and sphingosine 1-phosphate restores inter-endothelial communication. After that, STATs translocate into cell nucleus to orchestrate the expression of inflammatory cytokines, further instigating the cytokine storm feedback loop. Airway, lung parenchymal, pulmonary vascular, and respiratory neuromuscular disorders all feature in COVID-19. Article Unraveling the role of liver sinusoidal endothelial cells in COVID-19 liver injury. The authors declare no competing interests. The American-European Consensus Conference definition of the acute respiratory distress syndrome is dead, long live positive end-expiratory pressure! 2020;73:123140. SARS-CoV-2 infection relies on ACE2 expression in ECs [48]. 2021;133:489507. Unable to load your collection due to an error, Unable to load your delegates due to an error. Xing D, Liu Z. 2022;145:15035. 2021;63:103182. There are multiple lines of evidences suggesting the involvement of endothelial dysfunction in COVID-19 [45]. Fodor A, Tiperciuc B, Login C, Orasan OH, Lazar AL, Buchman C, et al. Recent randomized clinical trials revealed that treatment with fluvoxamine (a selective serotonin reuptake inhibitors, SSRI) reduced the need for COVID-19 hospitalization, reduced mortality and improved outcome over 15 days [148,149,150]. 2020;383:1208. Int J Infect Dis. Vitamin C is an essential, safe and inexpensive nutrient [152] that has anti-oxidant, anti-infectious, anti-inflammatory, anti-thrombotic and immune-modulatory effects [153]. IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome. 2022;23:6196. Front Med. 2021;40:101125. Biomedicines. 2022, https://doi.org/10.1002/ptr.7574. 2017;12:e0186116. In another translational study, treatment of human pluripotent stem cell-derived endothelial cells (hECs) with SARS-CoV-2 leads to enriched gene program involved in immunity, inflammation and viral response (such as TNF-, IFNs and NF-B signaling pathway). 2020;117:223516. Effects of Shuanghuanglian oral liquids on patients with COVID-19: a randomized, open-label, parallel-controlled, multicenter clinical trial. 2021;6:402. In addition, spike protein S1-mediated elevation of markers of endothelial inflammation and injury (including E-selectin, ICAM-1, VCAM-1 and PAI-1) and THP-1 monocyte adhesion to ECs was further exacerbated by dihydrotestosterone or TNF- treatment, but ameliorated by spironolactone treatment [77]. Zhang FS, He QZ, Qin CH, Little PJ, Weng JP, Xu SW. Further outstanding questions and research directions in the realm of endothelial dysfunction and COVID-19 include the following: The development of assays of assessing endothelial function in long COVID-19 patients and convalescents, such as brachial artery flow-mediated dilation (FMD) and arterial stiffness [carotid-femoral pulse wave velocity (cfPWV)]; This aspect is important considering the recent observation showing the decreased FMD in patients with COVID-19 stemming from expression of inflammatory cytokines/chemokines [176]; Cellular and animal models of evaluating endothelial dysfunction in COVID-19 to accelerate drug discovery; The therapeutic potential of specialized pro-resolving lipid mediators, such as resolvin D1, resolvin E1, aspirin-triggered resolvin D1 in resolving cytokine storm induced inflammatory responses can be pursued; The identification of alternative receptors for SARS-CoV-2 infection into different vascular beds beyond known ones (such as ACE2, AXL and L-SIGN) remain to be identified; Drug repurposing or high-throughput drug screening to identify new drugs targeting endothelial dysfunction in COVID-19; The role of epigenetic modification arising from DNA methylation and histone modification and long-lasting epigenetic memory effects caused by SARS-CoV2 infection in long COVID (postacute COVID-19 syndrome) remain to be evaluated [7]; Metabolic disturbance has been shown to be associated with the pathogenesis of COVID-19 [177]. 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. 2023 Apr 10;638:122941. doi: 10.1016/j.ijpharm.2023.122941. 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 is well-established that SARS-CoV-2 enters host cells including ECs via ACE2 and coreceptor TMPRSS2. 2022;10:812. de Rooij L, Becker LM, Carmeliet P. A role for the vascular endothelium in post-acute COVID-19? Circulatory exosomes from COVID-19 patients trigger NLRP3 inflammasome in endothelial cells. Lancet Glob Health. Lenze EJ, Mattar C, Zorumski CF, Stevens A, Schweiger J, Nicol GE, et al. Blood. Endothelial dysfunction in COVID-19: an overview of evidence, biomarkers, mechanisms and potential therapies. Ebihara T, Matsumoto H, Matsubara T, Togami Y, Nakao S, Matsuura H, et al. A recent study has shown that SARS-CoV-2 infection in humanized K18-hACE-2 mice activates the NLRP3 inflammasome, followed by caspase-1 and IL-1 activation[140]. It is possible that these cytokines will disrupt the integrity of various types of junctional proteins, including VE-cadherin, ZO-1, -catenin and gap junction proteins. 2022;43:217390. Cells. Copyright 2016 The Author. 2021;96:256175. 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 . Antihypertensive drug treatment and susceptibility to SARS-CoV-2 infection in human PSC-derived cardiomyocytes and primary endothelial cells. Potje SR, Costa TJ, Fraga-Silva TFC, Martins RB, Benatti MN, Almado CEL, et al.