Mechanic Forces Promote Brain Endothelial Activation by SARS-CoV-2 Spike Protein

HomeStrokeVol. 52, No. 1Mechanic Forces Promote Brain Endothelial Activation by SARS-CoV-2 Spike Protein Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBMechanic Aaron Babendreyer and Andreas Ludwig BabendreyerAaron Institute of Molecular Pharmacology, RWTH Aachen University, Germany. Search for more papers this author LudwigAndreas Correspondence to: Ludwig, PhD, Pauwelsstraße 30, 52074 Aachen, Email E-mail Address: [email protected] https://orcid.org/0000-0001-8536-4986 Originally published9 Nov 2020https://doi.org/10.1161/STROKEAHA.120.033119Stroke. 2021;52:271–273This article is a commentary on the followingFlow-Mediated Susceptibility Response Cerebral Endothelia InfectionOther version(s) articleYou are viewing most recent version article. Previous versions: November 9, 2020: Ahead Print The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces disease 2019 (COVID-19) air-borne infection nasal lung-epithelial cells. COVID-19 still increasing worldwide. Besides development antiviral therapy immunization, it essential gain detailed understanding novel clinical presentations that often reported.See related article, p 260The spike protein within lipid envelope binds ACE2 (angiotensin-converting enzyme 2).1 This interaction crucial viral infection.2 not only expressed in lung epithelium but also endothelial cells different organs including brain.3 Postmortem analysis revealed accompanied endothelitis several patients.4 Infection with associated an increased rate cerebrovascular events ischemic stroke intracerebral hemorrhage. supported rates even young patients COVID-19.5 molecular cellular mechanisms underlying risk need be better understood.In present issue, Kaneko et al6 report mRNA cultured primary derived from umbilical cord brain. Of note, 3-dimensional (3D) printed vascular culture model, expression much higher than monolayer culture. Moreover, perfusion 3D further upregulated ACE2-mRNA expression. upregulation was binding liposomes carrying recombinant protein. Such especially enhanced at sites stenosis. Finally, triggered gene transcription human brain complement component C3 (Figure).Download figureDownload PowerPointFigure. Model influence mechanical forces activation Both shear stress substrate properties promote 2) correlates protein, which then transcriptional changes, such as induction factor C3. process may mediated alone involve coreceptors, or proteases. For example, ADAM17 can activated SARS-CoV-2, turn leads shedding surface molecules, TNFα (tumor necrosis alpha), lead autocrine cell activation. shed switch off protective functions ACE2.The study clearly highlights great importance choose physiological conditions when studying cardiovascular model. It well known moderate flow causing induce number physiologically relevant genes, whereas proinflammatory genes supressed.7 instance, downregulate endothelin-1 prevent inflammatory chemokines adhesion molecules.8 Vice versa, many directly indirectly induced KLF2 (Kruppel-like pathway. These include NO synthase, thrombomodulin, ADAM15 (A disintegrin metalloproteinase 15).9 enzymatic activity counterregulates increase blood pressure reduces thrombogenicity. Thus, considered mechanism. prompts depth investigation mode regulation. mechanosensitive signaling pathway involved promoter. effects pathophysiological turbulent contrast laminar could investigated detail.Besides conditions, bed has significant impact biology cells.10 described stiffness influences various signal transduction pathways, Rho signaling, stiffer substrates found under fibrotic likely phenotype cells.11 Another deposition fibronectin, processes through integrins. In design study, these aspects explain inductive effect cultivation model alone. On one hand, significantly reduced using polydimethylsiloxane compared classical plastic, other integrin changed due fibronectin coating. Therefore, mimic biomechanical environment. fulfills issues appropriate conventional culture.At stenosis, confer protection allow via its indicated presented yet clear whether would fact contribute binding, interactions required infection. CD147 (basignin) discussed act another receptor epithelial lines.12 However, investigations sensitive assays confirm role basigin/CD147 alternative protein.13 Nevertheless, might parts larger complex rather independent receptors.14 undergo proteolytic processing TMPRSS2 (transmembrane protease, serine 2), critical event entry virus.2 additional accessory proteins coregulated stiffness. studied setting.Importantly, itself activate responses, this, virus necessary. Taken research warranted elucidate kinases factors. D614G mutation new variants bind original variant,15 needs clarified ACE2. been noted soluble form exists, generated limited proteolysis (shedding) surface. Members surface-expressed metalloproteinases (ADAMs) mediate membrane-expressed cytokines, growth factors, their receptors.16 vitro experiments indicate cleaved ADAM17.17 Even interesting, SARS-CoV-1 ADAM17-mediated ACE2.18 mechanism Additionally, cleavage junctional molecules thereby permeability. release TNF factor) factors positive feedback loop (Figure). indirect represent pathways leading changes were observed authors. Furthermore, reduce affect function. acting interact sodium-dependent amino acid transporter SIT1/B(0)AT1.19 Structural modeling suggested ACE2-B0AT1 simultaneously.20 By modifying complex, able response genes.In conclusion, data associates independently virus. direct potentially receptors enzymes. all COVID19 patients.Sources FundingThis supported, part, Bundesministerium für Bildung und Forschung (project 01KI20207) Deutsche Forschungsgemeinschaft 363055819/GRK2415 [ME3T] project C1).DisclosuresNone.FootnotesThe opinions necessarily those editors American Heart Association.For Disclosures, see page 273.Correspondence protected]deReferences1. Shang J, Ye G, Shi K, Wan Y, Luo C, Aihara H, Geng Q, Auerbach A, Li F. basis recognition SARS-CoV-2.Nature2020; 581:221–224. doi: 10.1038/s41586-020-2179-yCrossrefMedlineGoogle Scholar2. Hoffmann M, Kleine-Weber Schroeder S, Krüger N, Herrler T, Erichsen Schiergens TS, Wu NH, Nitsche al. 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Authors cited comment invited reply, appropriate.Comments AHA/ASA Scientific Statements Guidelines directed Manuscript Oversight Committee page.Sign Submit Article Back top Next FiguresReferencesRelatedDetailsRelated articlesFlow-Mediated InfectionNaoki Kaneko, Stroke. 2021;52:260-270 January 2021Vol Issue 1 Advertisement InformationMetrics © 2020 Association, Inc.https://doi.org/10.1161/STROKEAHA.120.033119PMID: 33161848 publishedNovember KeywordsbrainEditorialsextracellular matrixinflammationendothelial cellsPDF download SubjectsACE/Angiotensin Receptors/Renin Angiotensin SystemEndothelium/Vascular Type/Nitric OxideInflammationVascular Biology