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. Liu Y, Zhang HG. 2021;24:152233. COVID-19 and thermoregulation-related problems: Practical IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome. PEEP in COVID-19 Patients: A Retrospective Study on RV Dysfunction Risk of acute myocardial infarction and ischaemic stroke following COVID-19 in Sweden: a self-controlled case series and matched cohort study. The association between anti-diabetic agents and clinical outcomes of COVID-19 in patients with diabetes: a systematic review and meta-analysis. Long COVID Patients Respond Differently to COVID Vaccines - WebMD 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. J Neuroinflammation. Wenzel J, Lampe J, Mller-Fielitz H, Schuster R, Zille M, Mller K, et al. Chin Med. Liver injury in COVID-19 and IL-6 trans-signaling-induced endotheliopathy. Fajgenbaum DC, June CH. Gladka MM, Maack C. The endothelium as Achilles heel in COVID-19 patients. The SARS-CoV-2 main protease M(pro) causes microvascular brain pathology by cleaving NEMO in brain endothelial cells. Ebihara T, Matsumoto H, Matsubara T, Togami Y, Nakao S, Matsuura H, et al. Matarese A, Gambardella J, Sardu C, Santulli G. miR-98 regulates TMPRSS2 expression in human endothelial cells: key implications for COVID-19. This leads to decreased expression of VE-cadherin in lung endothelial cells. However, statin use can also induce the expression of ACE2, which may potentially increase virus entry [117]. Sur S, Steele R, Isbell TS, Ray R, Ray RB. Pathway enrichment analysis revealed that SARS-CoV-2 infection upregulates expression of genes enriched in signaling pathways relevant to inflammatory response (such as NF-kappa B signaling pathway, TLR signaling pathway, NLRP3 pathway, NOD-like receptor signaling pathway and cytokinecytokine receptor interaction) [75]. Villar J, Kacmarek RM. Breithaupt-Faloppa AC, Correia CJ, Prado CM, Stilhano RS, Ureshino RP, Moreira LFP. TCM has a well-documented safety profile in protecting against COVID-19 on the basis of standard care. Lenze EJ, Mattar C, Zorumski CF, Stevens A, Schweiger J, Nicol GE, et al. Theranostics. J Hepatol. 2022, https://doi.org/10.1002/ptr.7574. 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. 2020;32:17687. Kang S, Tanaka T, Inoue H, Ono C, Hashimoto S, Kioi Y, et al. Treatment of virus-infected human lung microvascular endothelial cells (HMVECs) with diminazene aceturate (an ACE2 agonist) reverses SARS-CoV-2 infection-induced hyperpermeability, indicating the possibility that ACE2 agonism indeed stabilizes endothelial barrier integrity without affecting viral uptake into ECs [23]. 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. 2022;13:916512. Semin Vasc Surg. 2021;7:9. Lancet (Lond, Engl). 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]. The existence of cytokine storm could trigger vascular leakage, endothelial permeability in particular. Interestingly, live SARS-CoV-2 virus and sera from COVID-19 patients, but not dead virus or spike protein triggers increased endothelial permeability [20, 23]. Endothelial cell infection and endotheliitis in COVID-19. Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. 2022;216:1204. 2020;26:101732. 2021;45:11639. SARS-CoV-2 infection can also cause acute kidney injury (AKI). Respir Med. 2020;159:105051. SARS-CoV-2 or viral proteins can infect endothelial cells and other host cells via reported receptors and the vicious cycle was perpetuated. Endothelial dysfunction in atherosclerotic cardiovascular diseases and beyond: from mechanism to pharmacotherapies. National Library of Medicine In a randomized clinical trial, L-arginine add-on therapy significantly reduces the length of hospitalization in severe COVID-19 patients and reduces the need of respiratory support, with no serious adverse events [147]. PubMed Central 2022;9:866113. Thrombosis Res. 2021;13:1172. 2021;221:153419. Persisting olfactory dysfunction in post-COVID-19 is associated - PLOS Rauti R, Shahoha M, Leichtmann-Bardoogo Y, Nasser R, Paz E, Tamir R, et al. Ikonomidis I, Pavlidis G, Katsimbri P, Lambadiari V, Parissis J, Andreadou I, et al. Ding Y, Zhou Y, Ling P, Feng X, Luo S, Zheng X, et al. 2021;41:277385. NO also has an anti-thrombotic action, by preventing leukocyte and platelet adhesion to activated endothelium, thereby inhibiting immunothrombosis and atherosclerotic plaque development [15]. Katsoularis I, Fonseca-Rodrguez O, Farrington P, Lindmark K, Fors Connolly AM. 2022;13:830061. Studies in the past two years altogether provide important mechanistic insights into the pathogenesis of COVID-19 and yield promising new therapeutic targets (Fig. Employing mechanical ventilation techniques on venovenous extracorporeal membrane oxygenation (VV ECMO . Zhang XJ, Qin JJ, Cheng X, Shen L, Zhao YC, Yuan Y, et al. Google Scholar. 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Effect of SARS-CoV-2 proteins on vascular permeability. 2022;9:844228. & Weng, Jp. Mol Neurobiol. Neurological implications of COVID-19: role of redox imbalance and mitochondrial dysfunction. Post-COVID-19 conditions alter a person's immune response Nagashima S, Mendes MC, Camargo Martins AP, Borges NH, Godoy TM, Miggiolaro A, et al. 2022;145:15035. ACE2 is highly expressed in renal tissues, the injury of which leads to proteinuria, hematuria and abnormal renal radiography [38]. 2020;116:166687. Thermoregulation is a vital function of the autonomic nervous system in response to cold and heat stress. volume44,pages 695709 (2023)Cite this article. Front Physiol. IL-6 directly impacts vascular ECs by promoting the production of numerous cytokines/chemokines/adhesion molecules essential for promoting leukocyte adhesion, vascular leakage and activating the coagulation cascade [136]. CAS Georg P, Astaburuaga-Garca R, Bonaguro L, Brumhard S, Michalick L, Lippert LJ, et al. 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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]. 2020;395:14178. 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These findings agree with a recent retrospective analysis by Zhang et al. Mayo Clin Proc. 2021;39:8201. Pathogenesis and Transmission of COVID-19. 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]. COVID-19-related neuropathology and microglial activation in elderly with and without dementia. 2020;10:2045894020966547. The pleiotropic effects of metformin help to control hyperglycemia, inhibit viral entry, and reduce inflammation following SARS-CoV-2 infection. 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. 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. Trends Microbiol. Front Med. A significant proportion of people who test positive for COVID-19 have chemosensory deficits. 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.
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