Recuperation of Vascular Homeostasis

HomeCirculation ResearchVol. 129, No. 2Recuperation of Vascular Homeostasis Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBRecuperation Andrea Huwiler and Josef Pfeilschifter HuwilerAndrea Correspondence to: Professor Huwiler, Institute Pharmacology, Inselspital INO-F, University Bern, Bern 3010, Switzerland. Email E-mail Address: [email protected] https://orcid.org/0000-0003-1615-5691 Switzerland (A.H.). Search for more papers by this author PfeilschifterJosef General Pharmacology Toxicology, Pharmazentrum Frankfurt/ZAFES, Goethe Frankfurt am Main, Germany (J.P.). Originally published8 Jul 2021https://doi.org/10.1161/CIRCRESAHA.121.319558Circulation Research. 2021;129:237–239This article is a commentary on the followingProgramming S1PR1+ Endothelial Cells Promotes Restoration IntegrityArticle, see p 221Homeostasis core concept resilient physiological systems that allows them successfully deal with 2 opposing fundamental tasks. On one hand, cells, organs, organisms have provide protection system, but other function as dynamically developing open systems, it equally important exchange fluids, salts, metabolites, information specific environment. To survive challenges continuously imposed these living environmental stress, sophisticated sensing mechanisms robust response strategies are required. Following an insult, body recruits powerful backup aim prevent loss control triggering mainly negative feedback regulatory pathways. As long injuries not overwhelming existent cellular defenses their severity or precipitancy onset, homeostasis will be reinstalled.The vascular endothelium prototype such homeostatic device. It serves maintain tissue fluid throughout regulating transport nutrients, water, immune cells. injury, example, endotoxin (lipopolysaccharide [LPS]), endothelial cells take measures delimit repair damage—a process known inflammation. However, intrinsic operative in reconstitute barrier functionality incompletely understood.Interestingly, sphingolipid signaling pathway its mediators focus recent interest key regulators homeostasis.1 Particularly, S1P (sphingosine 1-phosphate) G protein–coupled receptor S1PR1 (S1P subtype 1) been shown exert barrier-protective activity cells.2,3 Activation causes redistribution junctional proteins like VE-cadherin, ?-catenin, ?-catenin into areas cell-cell contact, thus tightening barrier. Moreover, application inhibits LPS-induced permeability lung brain.4,5 Two main isoforms sphingosine kinases, SPHK1 SPHK2, surprisingly quite distinct functions act generate messenger S1P. In turn, phosphatases lyase catalyze reversible irreversible degradation mediator, respectively. add further layer complexity, generated intracellularly, must exported out cell target surface receptors S1PR1.6,7 The system responsible transfer SPNS2 (spinster homology protein 2).8 Recently, was greatly impacts processes inflammation fibrosis.9,10Given importance S1P/S1PR1 device leakage edema formation, Akhter et al11 issue Circulation Research reported role S1PR1-positive (S1PR1+) controlling integrity injury repair.By challenging mice LPS, which acute leakage, they show new population upon has high regenerative capacity injured thereby restores (Figure).In elegant proof-of-concept transplantation approach, intravenously injected preisolated ECs from LPS-exposed S1PR1-GFP (green fluorescence protein) reporter LPS-treated EC-S1PR1?/? mice, integrated vessels.They demonstrate mechanism involves activation two transcription factors EGR1 (early growth 1 factor) STAT-3 (signal transducer activator 3) LPS. While mediates de novo synthesis produce S1P, drives expression SPNS2. Altogether, leads enhanced release extracellular milieu enhances, autocrine paracrine manner, restore Notably, direct selective agonist (CYM-5442) could bypass delayed seen LPS may represent way improve regeneration.With findings, we can begin appreciate sphingolipid-derived tool kits reinstall function. generation impressive capacity, after critical exposure, unravels facet repertoire reparative pathways.However, well-done studies invariably lead questions: particular, homing integration intravenous clear. Whether structural cues exposed matrix vessel downstream devices needs addressed future experiments. inconsistencies kinetics responses supposed linked form functional unit suggest complex at work. For instance, rapid phosphorylation 30 minutes stimulation 16 hours needed binding promoter simply due manner stated authors. Alternatively, intracellular flux sphingolipids through anabolic catabolic pathways promote by, sphingosine, ceramide, ceramide 1-phosphate, others. A potential cross-communication between TLR4 (toll-like 4) also context. addition, balance actions S1P10,12 critically influence overall response.Nevertheless, data basis several therapeutic treating diseases. clinicians basic scientists focused inflammatory illnesses, findings pose tackled experimentation studies.Download figureDownload PowerPointFigure. Schematic presentation steps involved reprogramming recuperation homeostasis. EC indicates cells; EGR1, early factor; lipopolysaccharide; pERK, phosphorylated signal-regulated kinase; pSTAT3, signal 3; 1-phosphate; S1PR1, 1; SPHK1, kinase SPNS2, spinster 2; TLR4, toll-like 4.Sources FundingThis work supported Swiss National Foundation (310030_175561/1 A. Huwiler) German (SFB1039 J. Pfeilschifter).Disclosures None.FootnotesThe opinions expressed necessarily those editors American Heart Association.For Sources Funding Disclosures, page 239.Correspondence andrea.[email protected]unibe.chReferences1. Proia RL, Hla T. Emerging biology sphingosine-1-phosphate: pathogenesis therapy.J Clin Invest. 2015; 125:1379–1387. doi: 10.1172/JCI76369CrossrefMedlineGoogle Scholar2. Skoura A, Regulation physiology pathology S1P2 subtype.Cardiovasc Res. 2009; 82:221–228. 10.1093/cvr/cvp088CrossrefMedlineGoogle Scholar3. Camerer E, Regard JB, Cornelissen I, Srinivasan Y, Duong DN, Palmer D, Pham TH, Wong JS, Pappu R, Coughlin SR. Sphingosine-1-phosphate plasma compartment regulates basal inflammation-induced leak mice.J 119:1871–1879. 10.1172/jci38575MedlineGoogle Scholar4. McVerry BJ, Garcia JG. regulation 1-phosphate.J Cell Biochem. 2004; 92:1075–1085. 10.1002/jcb.20088CrossrefMedlineGoogle Scholar5. Vutukuri Brunkhorst Kestner RI, Hansen L, Bouzas NF, J, Devraj K, W. 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