We also present emerging therapeutic agents and therapeutic targets which are directed at reducing the consequence of endothelial dysfunction/endotheliitis/endotheliopathy. Clipboard, Search History, and several other advanced features are temporarily unavailable. Pharmacol Res. 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. Google Scholar. SASP senescence-associated secretory phenotype. 1) . Angpt-2 angiopoietin-2, CCL2 chemokine (C-C motif) ligand 2, ECs endothelial cells, FMD flow-mediated dilation, HMWM high-molecular-weight multimers, IL-1 interleukin-1, IL-6 interleukin 6, PDGF-BB platelet-derived growth factor BB, s-Flt soluble fms-like tyrosine kinase, sICAM1 soluble ICAM1, sVCAM1 soluble VCAM1, sVE-cadherin soluble vascular endothelial cadherin, TF tissue factor, TNF- tumor necrosis factor, VEGF-A vascular endothelial growth factor A, vWF von Willebrand factor. Cell. Vasc Pharmacol. CAS and transmitted securely. Severe COVID-19 is a microvascular disease. A recent study  has reported that IL-6 trans-signaling in LSECs leads to endotheliopathy and liver injury in COVID-19 patients. In support of this finding, significantly higher level of angiogenesis was observed in lung tissues from COVID-19 patients, compared with patients with influenza . mydriasis, hypotension, and muscle dysfunction, which can progress to cardiac arrest or coma. Mller R, Rink G, Uzun G, Bakchoul T, Wuchter P, Klter H, et al. 2020;383:225573. 2020;75:e1980. 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 . These findings suggest that fluvoxamine can be repurposed as novel anti-COVID-19 drugs although further studies are warranted to assess the therapeutic potential of fluvoxamine in patients . 2014;120:947-57. doi: 10.1016/B978-0-7020-4087-0.00062-0. Circulation. Huet T, Beaussier H, Voisin O, Jouveshomme S, Dauriat G, Lazareth I, et al. Combinatorial treatment of human ECs with TNF- and IFN- increased the expression of ACE2, the receptor mediating viral entry via JAK/STAT1 pathway . 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. 2020;5:e138070. J Infect Dis. A new study by investigators from the Smidt Heart Institute at Cedars-Sinai suggests long COVID-19 might be caused by a dysfunction of . During the course of COVID-19 pneumonia, thyrotoxicosis may be caused secondary to graves thyroiditis or subacute inflammatory thyroiditis. The most common clinical presentation of severe COVID-19 is acute respiratory failure consistent with the acute respiratory distress syndrome. Kang S, Kishimoto T. Interplay between interleukin-6 signaling and the vascular endothelium in cytokine storms. Recently, miR-98-5p was identified as a negative regulator of TMPRSS2 gene transcription in human lung and umbilical vein ECs . Endothelial contribution to COVID-19: an update on mechanisms and therapeutic implications. Ilonzo N, Judelson D, Al-Jundi W, Etkin Y, OBanion LA, Rivera A, et al. PubMed Cytokine storm. Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, et al. 2021;4:e2133090. . J Virol.  and the expert recommendations from the professional cardiovascular societies, supporting that ACEIs and ARBs does not alter SARS-CoV-2 infection and should not be discontinued in COVID-19 patients . These findings suggest that spike protein interactions with ECs contribute to inflammation, thrombosis, and the severity of COVID-19 and could offer novel mechanistic insights into SARS-CoV-2 induced vascular leakage and the development of targeted therapies . 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  in light of elevated circulating level of biomarker soluble P-selectin in COVID-19 convalescent donors compared to healthy controls . SARS-CoV-2 infection remodels the phenotype and promotes angiogenesis of primary human lung endothelial cells. Schnaubelt S, Oppenauer J, Tihanyi D, Mueller M, Maldonado-Gonzalez E, Zejnilovic S, et al. 2022;54:102362. Breithaupt-Faloppa AC, Correia CJ, Prado CM, Stilhano RS, Ureshino RP, Moreira LFP. Int J Infect Dis. The therapeutic potential of senolytics in COVID-19 patients warrants studies from clinical trials. Endothelial cell number is determined by the balance of cell proliferation and cell death. Am J Respiratory Cell Mol Biol. The elevated VEGF-A level further promotes endothelial leakage and inflammatory cell infiltration . Results of the first interim analysis. 2021;12:653110. Endothelial integrity is essential for maintaining the pulmonary capillary-alveolar barrier and lung homoeostasis. In this study we assessed both olfaction and gustation using psychophysical tests eight months after COVID-19. Further, removal of the N-glycosylation site at N92 of L-SIGN enhances the binding of S-RBD with L-SIGN . Vasc Pharmacol. It is reported that under normal conditions, pulmonary ECs express minimal level of ACE2. Gladka MM, Maack C. The endothelium as Achilles heel in COVID-19 patients. 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. 2021;11:807691. 2022;75:103812. Liu Y, Zhang HG. Recent studies have suggested that LSEC dysfunction is involved in COVID-19 associated liver injury . Theranostics. An official website of the United States government. Targeting endothelial dysfunction in eight extreme-critically ill patients with COVID-19 using the anti-adrenomedullin antibody adrecizumab (HAM8101). After virus infection, ensuing cytokine storm occurs in severe COVID-19 patients, particularly the elevated secretion of pro-inflammatory cytokine interleukin 6 (IL-6). The fight against coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is still raging. N Engl J Med. The PAI-1 level in COVID-19 patients were as highly elevated compared with other cytokine release syndrome (sepsis or ARDS). You are using a browser version with limited support for CSS. Under physiological conditions, ECs undergoing apoptotic process are released into circulating blood. 2022;96:3441. 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 . Mitochondria is an important organelle that regulates antioxidant/redox signaling, by fine-tuning mitochondria-derived reactive oxygen species (mtROS) production. To obtain 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 . Insights into endotheliopathy in COVID-19. Pulmonary capillary endothelium provides a fertile soil for viral entry, replication, thereby facilitating viral entry to the circulating blood [19, 20]. 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 ; 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 ; Metabolic disturbance has been shown to be associated with the pathogenesis of COVID-19 . https://doi.org/10.1038/s41401-022-00998-0, DOI: https://doi.org/10.1038/s41401-022-00998-0. 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 . The SARS-CoV-2 main protease M(pro) causes microvascular brain pathology by cleaving NEMO in brain endothelial cells. A recent multi-omics study has revealed that COVID-19 associated AKI resembles AKI induced by sepsis, which involves the mechanism of mitochondria dysfunction, inflammation, necroptosis, capillary congestion and endothelial injury . Torices S, Motta C, da Rosa B, Marcos A, Alvarez-Rosa L, Siqueira M, et al. PubMed Google Scholar. The infected cell releases danger signals leading to multiple aspects of endothelial dysfunction, which finally leads to impaired vascular activity and multi-organ injury. Endothelial to mesenchymal transition: a precursor to post-COVID-19 interstitial pulmonary fibrosis and vascular obliteration? Avoidance of thermal risk and early recognition of cold or heat stress are the cornerstones of preventive therapy. Fiorentino G, Coppola A, Izzo R, Annunziata A, Bernardo M, Lombardi A, et al. Xu, Sw., Ilyas, I. Anakinra treatment reduced both the need for mechanical ventilation in patients admitted to ICU and mortality of severe COVID-19 patients, with good safety profile , especially in patients with CRP concentrations >100mg/L . 2022;17:30. Adv Exp Med Biol. Biomolecules. Thermoregulatory dysfunction is defined as significant loss of a person's capacity to control body temperature, and the medical conditions which result in the person's health and bodily function being seriously affected when exposed to extremes of environmental temperatures. These evidences signify their potential prognostic value to predict severity and mortality of COVID-19 [103, 107]. Anakinra, by blocking interleukin 1 receptor, prevented VE-cadherin downregulation and lung vascular leakage. Medicine (Baltimore). Therapeutic potential of megadose vitamin C to reverse organ dysfunction in sepsis and COVID-19. Zhang FS, He QZ, Qin CH, Little PJ, Weng JP, Xu SW. Eur J Intern Med. Direct or indirect mechanisms are operating to collectively indicate the alterations in vascular homeostasis in COVID-19 . 6). Lancet Rheumatol. The IL-1, IL-6, and TNF cytokine triad is associated with post-acute sequelae of COVID-19. QJM. Elevated expression of serum endothelial cell adhesion molecules in COVID-19 patients. 2020;117:223516. 7). Role of traditional chinese medicine in treating severe or critical covid-19: a systematic review of randomized controlled trials and observational studies. Direct or indirect mechanism after SARS-CoV-2 infection and the consequent endotheliitis/endotheliopathy incites multiple instances of endothelial dysfunction, including altered vascular tone, oxidative stress, inflammation/leukocyte adhesion, endothelial mesenchymal transition (EndoMT), mitochondria dysfunction, virus-induced senescence, cytokine storm, and coagulopathy [12, 13]. 2021;178:38648. Anti-SARS-CoV-2 action of fluvoxamine may be mediated by endothelial nitric oxide synthase. Batabyal R, Freishtat N, Hill E, Rehman M, Freishtat R, Koutroulis I. Metabolic dysfunction and immunometabolism in COVID-19 pathophysiology and therapeutics. COVID-19 can manifest with myocardial injury (ischemic heart disease, arrhythmias and cardiomyopathies), arterial stiffness, liver injury and kidney injury . Increased heparanase activity and heparan sulphate level have been observed in plasma derived from COVID-19 patients . Eur Heart J. Deaths from hypothermia are twice as frequent as deaths from hyperthermia. Therefore, ACE2 expression may have paradoxical effects, aiding SARS-CoV-2 pathogenicity, yet conversely limiting viral infection [87, 130]. The pathophysiology, impact, and outcomes of hyperpyrexia in patients with COVID-19 have not yet been studied. Endothelial dysfunction-induced endotheliitis/endothelialitis/endotheliopathy following SARS-CoV-2 infection arises from a plethora of physiopathological mechanisms, including both direct mechanism of virus infection or indirect mechanisms such as paracrine effects of infected cells [2, 68]. SARS-CoV-2 Spike triggers barrier dysfunction and vascular leak via integrins and TGF- signaling. Caccuri F, Bugatti A, Zani A, De Palma A, Di Silvestre D, Manocha E, et al. Wu D, Lee TH, Huang RT, D Guzy R, Schoettler N, Adegunsoye A, et al. Meyer K, Patra T, Vijayamahantesh, Ray R. SARS-CoV-2 spike protein induces paracrine senescence and leukocyte adhesion in endothelial cells. In addition, a recent study has shown that circulating level of ET-1, a potent vasoconstrictive peptide, was elevated in hospitalized patients with acute phase of COVID-19, indicating that ET-1 receptor blockers could potentially offer clinical benefits for COVID-19 patients . Redox Biol. In addition, the release of inflammatory cytokines after severe SARS-CoV-2 infection leads to cytokine storm, tight junction barrier disruption, pulmonary hypertension, and lung fibrosis . Endothelin-1 is increased in the plasma of patients hospitalised with Covid-19. 2022;9:866113. Front Endocrinol. Food Chem Toxicol. 2021;13:2209. 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. In the meantime, to ensure continued support, we are displaying the site without styles 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. Ebihara T, Matsumoto H, Matsubara T, Togami Y, Nakao S, Matsuura H, et al. Bethesda, MD 20894, Web Policies Wenzel J, Lampe J, Mller-Fielitz H, Schuster R, Zille M, Mller K, et al. Epub 2023 Jan 6. Diabetes/hyperglycemia further exacerbate pre-existing endothelial dysfunction and hyperinflammation in COVID-19 patients. Bauersachs J, de Boer RA, Lindenfeld J, Bozkurt B. It has been recently reviewed that restoration of balanced effects between the RAAS and ACE2/Ang-(17)/MAS could be a promising way to ameliorate multi-organ injury associated with COVID-19 . Circulating endothelial cells as a marker of endothelial injury in severe COVID -19. Lee S, Yu Y, Trimpert J, Benthani F, Mairhofer M, Richter-Pechanska P, et al. 2208085J08) and Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (Grant No. Med Intensiv. The thermoregulation system includes the hypothalamus in the brain, as well as the sweat. Li F, Li J, Wang PH, Yang N, Huang J, Ou J, et al. These data agree with recent report of the clinical benefits of statin therapy in lowering the risk of mortality of COVID-19 . 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 . 01 May 2023 01:18:34 2022;10:e42e51. 2021;24:152233. Intern Emerg Med. ISSN 1745-7254 (online) 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. 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. COVID-19-Associated lung microvascular endotheliopathy: a from the bench perspective. These effects were blocked by soluble glycoprotein 130, ruxolitinib, and STAT1/3 depletion. Aging Dis. ACE2 can also undergo shedding and the soluble form of ACE2 (sACE2) can be released into circulating blood. Filbin MR. Vigilance on new-onset atherosclerosis following SARS-CoV-2 infection. Saviano A, Baumert TF. Inhibition of heparanase by a non-anticoagulant heparin fragment prevented glycocalyx destruction in response to COVID-19 serum treatment . 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 reported that COVID-19-patients had higher number of CECs than COVID-19-free subjects. Syndecan-1, an important vascular component of glycocalyx released after vasculitis and injury, well correlates with the marker of coagulation (D-dimer) in particular. The glycocalyx is a proteoglycan- and glycoprotein-rich microstructure covering ECs essential for maintaining vascular homeostasis via regulating vascular tone, permeability, thrombosis and leukocyte adhesion to endothelium . Nutrients. Thus, hyperinflammation and inflammasome activation associated with SARS-CoV-2 infection will lead to endothelial cell injury and death (such as pyroptosis). Google Scholar. PubMed Therefore, IL-6 trans-signaling represents the mechanistic link between the coagulopathy/endotheliopathy and COVID-19 associated liver injury . Postgrad Med. This study highlights the crucial role of IL-6 trans-signaling in endothelial dysfunction/endotheliopathy in COVID-19 . 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. Analysis of ACE2 expression in autopsy tissues indicates that high expression of ACE2, transmembrane protease serine 2 (TMPRSS2) and associated endotheliitis in capillaries but less in arterioles/venules from COVID-19 patients, compared with COVID-19-free subjects. Syndecan-1, an indicator of endothelial glycocalyx degradation, predicts outcome of patients admitted to an ICU with COVID-19. CD209L/L-SIGN and CD209/DC-SIGN act as receptors for SARS-CoV-2. 2021;16:e0254167. Xu S, Ilyas I, Little PJ, Li H, Kamato D, Zheng X, et al. JCI insight. 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. JCI insight. Thermoregulatory physiology sustains health by keeping body core temperature within a degree or two of 37C, which enables normal cellular function.