Henry BM, de Oliveira MHS, Cheruiyot I, Benoit JL, Cooper DS, Lippi G, 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-. Researchers from the University of Milan, Italy have found a link between thyroid dysfunction and moderate-to-severe COVID-19. Google Scholar. 2021;22:4177. Mayo Clin Proc. Unexpectedly, propensity score-weighted analysis showed that treatment with ACEI/ARB was not significantly associated with the occurrence of defined end-points. Cell Rep Med. NO is one of the most important vasodilatory substances produced by the vascular endothelium with the action of the endothelial NO synthase (eNOS) and several cofactors. 2021;11:807691. Therefore, primary endothelial cell senescence or secondary senescence caused by SRAS-CoV-2 infected non-ECs can be exploited as a new therapeutic target for ameliorating COVID-19 associated endotheliitis [90]. FOIA Liu Y, Zhang HG. Validated psychophysical testing revealed hyposmia in 18% and hypogeusia in even 32% of 303 included patients. sharing sensitive information, make sure youre on a federal Fiziol Zh Im I M Sechenova. However, pre-treatment of ECs with losartan (belonging to ARB) and lisinopril (belonging to ACEI), fail to affect the susceptibility of hEC to SARS-CoV-2 infection [131]. 2022;23:6196. 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. Zhang L, Zhou L, Bao L, Liu J, Zhu H, Lv Q, et al. Arq Bras Cardiol. When endothelial dysfunction/endotheliopathy/endotheliitis occurs in COVID-19, several markers of endothelial cell activation are used for assessing endothelial dysfunction in COVID-19 (Figs. Handb Clin Neurol. 2022;3:100663. The levels of biomarkers of endothelial cell activation/injury well correlate with the expression level of pro-inflammatory cytokines and chemokines [103]. 2020;324:2292300. Endothelial dysfunction is generally defined as decreased NO bioavailability and an increase in vasoconstrictory substances (such as endothelin-1 (ET1), angiotensin II (AngII) and many others). The association between anti-diabetic agents and clinical outcomes of COVID-19 in patients with diabetes: a systematic review and meta-analysis. Thus, the endothelium is regarded as the Achilles heel in COVID-19 patients [8]. ACE2 can also undergo shedding and the soluble form of ACE2 (sACE2) can be released into circulating blood. Disclaimer. Pulm Circ. 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]. These effects were blocked by soluble glycoprotein 130, ruxolitinib, and STAT1/3 depletion. Xu S, Liu Y, Ding Y, Luo S, Zheng X, Wu X, et al. Pharmacol Res. SARS-CoV-2 infection relies on ACE2 expression in ECs [48]. The Sexual Long COVID (SLC): Erectile Dysfunction as a Biomarker of Systemic Complications for COVID-19 Long Haulers - PubMed. Katsoularis I, Fonseca-Rodrguez O, Farrington P, Lindmark K, Fors Connolly AM. Endothelial cells are not productively infected by SARS-CoV-2. ICU admission levels of endothelial biomarkers as predictors of mortality in critically Ill COVID-19 patients. 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. Beneficial effects of mineralocorticoid receptor pathway blockade against endothelial inflammation induced by SARS-CoV-2 spike protein. eLife. N Engl J Med. Ngele MP, Haubner B, Tanner FC, Ruschitzka F, Flammer AJ. A recent study [35] has reported that IL-6 trans-signaling in LSECs leads to endotheliopathy and liver injury in COVID-19 patients. 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]. Vitamin C and COVID-19. 2021;164:6982. Deaths from . Vasculopathy in COVID-19. Schattner A. Colchicine-new horizons for an ancient drug. SARS-CoV-2 spike protein induces degradation of junctional proteins that maintain endothelial barrier integrity. 2022;10:e42e51. Eur Heart J. J Thrombosis Haemost. Circ Res. An unresolved question. Direct activation of endothelial cells by SARS-CoV-2 nucleocapsid protein is blocked by simvastatin. Chen S, Zheng C, Chen T, Huang D, Pan Y, Chen S. Relationship between plasma vitamin C and COVID-19 susceptibility and severity: a two-sample mendelian randomization study. Trends Microbiol. Hyperpyrexia is an elevation of body temperature above 106.7F (41.5C) due to an abnormally increased hypothalamic-thermoregulatory set. The endothelium, the widely-distributed organ of the human body, is essential for maintaining tissue homeostasis by producing a variety of vasoactive molecules. Targeting endothelial dysfunction in eight extreme-critically ill patients with COVID-19 using the anti-adrenomedullin antibody adrecizumab (HAM8101). 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]. SARS-CoV-2 infection can also cause acute kidney injury (AKI). The vascular endothelium, the innermost layer of blood vessels, provides a dynamic interface between the circulating blood and various tissues/organs and thereby maintaining tissue homeostasis. The site is secure. 2022;55:57. Injury to the endothelial glycocalyx in critically Ill patients with COVID-19. The endothelium and COVID-19: an increasingly clear link brief title: endotheliopathy in COVID-19. 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]. Endothelial thrombomodulin downregulation caused by hypoxia contributes to severe infiltration and coagulopathy in COVID-19 patient lungs. 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. 2021;1321:3343. SARS-CoV-2 Spike triggers barrier dysfunction and vascular leak via integrins and TGF- signaling. 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]. Bhowmik KK, Barek MA, Aziz MA, Islam MS. Impact of high-dose vitamin C on the mortality, severity, and duration of hospital stay in COVID-19 patients: a meta-analysis. Even in convalescent COVID-19 patients, the level of SDC-1 levels was significantly elevated compared to healthy controls, demonstrating the existence of persistent endothelial damage after severe COVID-19 progression [71]. 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. Anakinra, by blocking interleukin 1 receptor, prevented VE-cadherin downregulation and lung vascular leakage. Furthermore, spike protein S1 receptor-binding domain (S1-RBD) infection in mouse brain microvascular ECs induced the degradation of endothelial junctional proteins (VE-Cadherin, junctional adhesion molecule-A, Connexin-43 and PECAM-1), thereby impaired endothelial barrier function and caused vascular leakage and endotheliitis in COVID-19 patients [57, 58]. 2021;375:n2400. Based on the evidence presented, there was heterogenous ACE2 expression in ECs from various vascular beds. Dupont A, Rauch A, Staessens S, Moussa M, Rosa M, Corseaux D, et al. 1996 Oct-Nov;82(10-11):108-14. 2021;16:e0254167. Mechanistically, L-SIGN interacted with high-mannose-type N-glycans on the receptor-binding domain of SARS-CoV-2 spike protein in a Ca2+-dependent manner [33]. SARS-CoV-2 mediated endothelial dysfunction: the potential role of chronic oxidative stress. PubMed Central PubMedGoogle Scholar. Further, removal of the N-glycosylation site at N92 of L-SIGN enhances the binding of S-RBD with L-SIGN [21]. J Hepatol. Infection with various types of viruses, including SARS-CoV-2, can trigger endothelial senescence. Virus-induced senescence is a driver and therapeutic target in COVID-19. The .gov means its official. Therefore, emerging therapies targeting endothelial dysfunction and endotheliopathy are hopeful to ameliorate COVID-19 associated lung injury [25]. 2020;142:160911. In line with this finding, a recent study has demonstrated that human brain microvascular endothelial cells (hBMECs) infected with SARS-CoV-2 display heightened expression of pro-inflammatory cytokines/chemokines/adhesion molecules (such as TNF-, IL-1, MCP-1, CXCL1, CXCL8, CD40, CD44, ICAM1 and VCAM1, etc) and endothelial activation [75]. Mol Neurobiol. 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]. 2020;98:31422. As well, nAChR activators through interaction with diverse signaling pathways can reduce the risk of inflammatory disorders in COVID-19. Cecon E, Fernandois D, Renault N, Coelho CFF, Wenzel J, Bedart C, et al. DAgnillo F, Walters KA, Xiao Y, Sheng ZM, Scherler K, Park J, et al. In COVID-19 patients, heart failure and myocardial injury are frequent complications, underscoring the clinical utility of SGLT2 inhibitors [128]. Pharmacopsychiatry. Pharmacol Rev. Impact of sodium glucose cotransporter 2 (SGLT2) inhibitors on atherosclerosis: from pharmacology to pre-clinical and clinical therapeutics. 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]. Shao Y, Saredy J, Xu K, Sun Y, Saaoud F, Drummer CT, et al. Before Corrao S, Pinelli K, Vacca M, Raspanti M, Argano C. Type 2 diabetes mellitus and COVID-19: a narrative review. Von Willebrand factor: A key glycoprotein involved in thrombo-inflammatory complications of COVID-19. In addition to mtROS, other sources of ROS can also be possible, such as ROS derived from NADPH oxidase activation as well as eNOS uncoupling [85]. 2021;107:2323. J Intern Med. Liver injury in COVID-19 and IL-6 trans-signaling-induced endotheliopathy. HIVC improves myocardial injury via decreasing biomarkers associated with inflammation in critically ill COVID-19 patients [155]. 6). Pan R, Xie M, Chen M, Zhang Y, Ma J, Zhou J. 2021;13:2209. JAMA. The thermoregulation system includes the hypothalamus in the brain, as well as the sweat. A recent study has shown that increased levels of cellular senescence-associated markers, including PAI-1, p21 and sirtuin-1 in patient serum as well as lung ECs [89]. Google Scholar. Endothelial dysfunction, inflammation, and oxidative stress in COVID-19-mechanisms and therapeutic targets. Therefore, maintaining the integrity of glycocalyx offers new strategies to combat COVID-19 associated endothelial dysfunction [114]. Correspondence to It is well-recognized that patients with type 2 diabetes mellitus (T2DM) present with increased COVID-19 severity and poorer clinical outcomes compared with non-diabetic subjects [122]. An analysis of patients with a chief complaint of difficulty moving. However, the underlying cellular and molecular mechanisms driving this condition are . Circulation. Sulodexide significantly improves endothelial dysfunction and alleviates chest pain and palpitations in patients with long-COVID-19: Insights From TUN-EndCOV study. Brain Pathol (Zur, Switz). CD209L/L-SIGN and CD209/DC-SIGN act as receptors for SARS-CoV-2. 2021;13:2090614. PLoS One. These data agree with recent report of the clinical benefits of statin therapy in lowering the risk of mortality of COVID-19 [119]. 2021;53:18695. Activated cytokine storm and IL-6 signaling has been observed in endothelial dysfunction during bacterial infection and SARS-CoV-2 infection [92]. [The initiation of cold shivering during the local heating of the rat hypothalamus under immersion hypothermia]. Cellular senescence was also associated with endothelial inflammation (augmented expression of ICAM-1 and VCAM-1), which is essential for promoting leukocyte adhesion to activated endothelium. Redox Biol. 5. Cardiovasc Res. Circulation. 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]. Cell Res. CAS While COVID-19 primarily affects the lungs, it also affects other organs, the heart in particular. Like other types of cell senescence, virus-induced senescence is associated with senescence-associated secretory phenotype (SASP), which is evidenced by increased secretion of pro-inflammatory cytokines, pro-coagulatory factors and VEGF. 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. 2021;6:e148999. The IL-1, IL-6, and TNF cytokine triad is associated with post-acute sequelae of COVID-19. Cytokine. Moretta P, Maniscalco M, Papa A, Lanzillo A, Trojano L, Ambrosino P. Cognitive impairment and endothelial dysfunction in convalescent COVID-19 patients undergoing rehabilitation. XDB38010100). It is reported that COVID-19-patients had higher number of CECs than COVID-19-free subjects. The American-European Consensus Conference definition of the acute respiratory distress syndrome is dead, long live positive end-expiratory pressure! 2022;75:103812. 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]. Onorato D, Pucci M, Carpene G, Henry BM, Sanchis-Gomar F, Lippi G. Protective effects of statins administration in European and North American patients infected with COVID-19: a meta-analysis. Jothimani D, Venugopal R, Abedin MF, Kaliamoorthy I, Rela M. COVID-19 and the liver. COVID-19 and Endothelial Cell Dysfunction Initial SARS-CoV-2 infection occurs within the lung epithelia, whereby serine proteases, most notably transmembrane protease serine 2 (TMPRSS2), cathepsin B, and cathepsin L1, prime the SARS-CoV-2 spike glycoprotein, which is followed by ACE2-mediated viral entry ( 29 ). Free Radic Biol Med. Cell. 3). Kim WY, Kweon OJ, Cha MJ, Baek MS, Choi SH. 2020;10:1171. SARS-CoV-2 and COVID-19: The most important research questions. 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. and transmitted securely. Jover E, Matilla L, Garaikoetxea M, Fernndez-Celis A, Muntendam P, Jaisser F, et al. 2021YFC2500500), National Natural Science Foundation of China (Grant No. Thank you for visiting nature.com. It remains elusive whether COVID-19 patient should continue or initiate statin therapy. Front Immunol. Front Environ Sci Eng. However, statin use can also induce the expression of ACE2, which may potentially increase virus entry [117]. 2021;31:41532. 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. EndoMT, defined as the loss of endothelial markers/characteristics (CD31, VE-cadherin and Tie2) and gaining of mesenchymal cell markers (FSP-1, -SMA and vimentin), is central to COVID-19 induced lung fibrosis and pulmonary artery hypertension [72, 73].