FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4313506721> ?p ?o ?g. }

• W4313506721 endingPage "214" @default.
• W4313506721 startingPage "212" @default.
• W4313506721 abstract "HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 43, No. 2“Cre”ating New Tools for Smooth Muscle Analysis Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUB“Cre”ating New Tools for Smooth Muscle Analysis Brendan J. O’Brien, Kathleen A. Martin and Stefan Offermanns Brendan J. O’BrienBrendan J. O’Brien https://orcid.org/0000-0001-9425-7832 Departments of Medicine (Cardiovascular Medicine) and Pharmacology, Yale University School of Medicine, New Haven, CT (B.J.O., K.A.M.). Search for more papers by this author , Kathleen A. MartinKathleen A. Martin Correspondence to: Kathleen A. Martin, PhD, Yale Cardiovascular Research Center, 300 George St, Suite 759, New Haven, CT 06510. Email E-mail Address: [email protected] https://orcid.org/0000-0002-1748-0034 Departments of Medicine (Cardiovascular Medicine) and Pharmacology, Yale University School of Medicine, New Haven, CT (B.J.O., K.A.M.). Search for more papers by this author and Stefan OffermannsStefan Offermanns https://orcid.org/0000-0001-8676-6805 Max Planck Institute for Heart and Lung Research, Bad Nauheim and Center for Molecular Medicine, Goethe University, Frankfurt, Germany (S.O.). Search for more papers by this author Originally published5 Jan 2023https://doi.org/10.1161/ATVBAHA.122.318855Arteriosclerosis, Thrombosis, and Vascular Biology. 2023;43:212–214is related toA New Autosomal Myh11-CreERT2 Smooth Muscle Cell Lineage Tracing and Gene Knockout Mouse Model—Brief ReportOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 5, 2023: Ahead of Print Smooth muscle cells (SMCs) form the muscular layer of blood vessels and the viscera in the gastrointestinal, urinary, and reproductive systems and airways. These quiescent differentiated myocytes retain a remarkable plasticity that allows for vascular remodeling and repair. In response to injury, inflammation, or hypercholesterolemia, vascular SMCs can dedifferentiate and proliferate as a protective response but when unchecked, can drive intimal hyperplasia, atherosclerosis, and other pathologies.1,2See accompanying article on page 203Because dedifferentiated SMCs profoundly downregulate expression of their hallmark SMC-specific contractile proteins, the roles of SMCs in cardiovascular disease were underestimated until the advent of lineage tracing approaches. Permanent genetic marking of mature SMCs using the Cre (causes recombination)-loxP (locus of crossing [x] over, P1) DNA recombination system revealed that differentiated SMCs can give rise to a broad spectrum of phenotypes including cells resembling macrophages, fibroblasts, adipocytes,3 osteochondrocytes,4 and stem cells.5 These observations have led to fundamental advances in SMC biology. Paradigm-shifting revelations included confirmation that SMCs clonally expand to form lesions in atherosclerosis and intimal hyperplasia6–8 and the discovery that up to ≈60% of macrophage-like cells in atherosclerotic plaques are SMC-derived.9Although the commonly used Cre lines that direct expression to SMCs have been invaluable, expression of these alleles in other cell types has also been documented (comprehensively reviewed in Chakraborty et al10). Tagln(SM22α)-Cre drivers, for example, express in the embryonic heart, as well as in adipocytes, myeloid cells, and platelets.10 An Acta2CreERT2 line that expresses in vascular and visceral SMCs in males and females11 has been the preferred tool for studies of arteriole hypermuscularization in pulmonary hypertension12,13 but also expresses in myofibroblasts and myoepithelial cells.10 The Myh11-CreERT2-Off mouse line,14 considered the gold standard, has been extensively used for inducible SMC-specific Cre/loxP-mediated recombination in conditional mutagenesis or lineage tracing experiments. This line specifically recombines in vascular and visceral SMCs as well as in pericytes, underscoring the fact that MYH11, encoding the smooth muscle myosin heavy chain, is still the most specific marker for differentiated SMCs.15,16 However, this bacterial artificial chromosome–based mouse line carries the transgene on the Y-chromosome, which precludes analysis in females.In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Deaton et al17 describe the generation of a novel bacterial artificial chromosome–based Myh11-CreERT2-RAD mouse line, in which bacterial artificial chromosome insertion occurred on chromosome 2. The authors present a rigorous side-by-side analysis of the old and the new Myh11-CreERT2 mouse lines and provide robust data indicating that the new line is equivalent to the original with the advantage of allowing experiments in male and in female Myh11-CreERT2 mice (Figure 1). This is highly significant given the pressing need to understand the basis of sex differences in cardiovascular disease.18Download figureDownload PowerPointFigure 1. Comparison of smooth muscle–specific Cre lines. Murine Cre driver lines are identified above each panel with chromosome location and method of strain generation. Panels summarize the published expression patterns of each specific Cre recombinase, with red color corresponding to intensity of expression in vascular and visceral smooth muscle, which is also described in text below. Note that coronary, pulmonary, and peripheral vasculature are not illustrated for simplicity. Expression in cells other than vascular or visceral smooth muscle cells (SMCs) is illustrated by organs and arrows, with numbers corresponding to the cell types listed below each panel (superscript numbers indicate references). The patterns of tissue expression for each line are the same in males and females for the Myh11-CreERT2-RAD and Itga8-CreERT2 except for in the female reproductive organs indicated. Expression in the Myh11-CreERT2-Off line is limited to male mice only. BAC indicates bacterial artificial chromosome; Chr, chromosome; and GI, gastrointestinal. Figure created with BioRender.com.23,24Is this mouse line now the ultimate tool to perform conditional mutagenesis and lineage tracing in SMCs? Yes, and no. Although providing an important advantage, the new Myh11-CreERT2-RAD line can still have limitations depending on experimental design. CreERT2 expression driven by the Myh11 promoter results in relatively high CreERT2 protein levels, ensuring efficient tamoxifen-dependent recombination. However, it also results in a small degree of tamoxifen-independent recombination, which accumulates over time and, especially in aged mice, can reach considerable levels of recombination in the absence of tamoxifen. This leakiness is SMC-specific and is also seen in the original Myh11-CreERT2-Off line.17 It is most likely due to a small fraction of the CreERT2 protein which escapes the cytoplasmic sequestration mechanisms in the absence of tamoxifen, including binding to heat shock protein 90, and then translocates to the nucleus. Interestingly, Deaton et al17 demonstrated that the degree of age-dependent tamoxifen-independent recombination varies between different floxed alleles. Thus, tamoxifen-independent recombination, which has been observed in many CreERT2-driver mice,19 requires appropriate controls, especially when working with older mice. Although not yet reported in smooth muscle–specific Cre driver lines, there is also potential for toxicity mediated solely by Cre/CreERT2 expression.20 It is, therefore, recommended when using inducible conditional Cre/loxP-mediated strategies to control not only for CreERT2-independent tamoxifen effects but also for potential CreERT2 toxicity by including CreERT2-positive mice lacking the floxed allele in the analysis.Another potential problem arises from the ability of Myh11-CreERT2 mice to recombine floxed alleles in both vascular and visceral SMCs. This can lead to visceral pathologies so severe or even lethal that analysis of vascular phenotypes is impossible. In this case, a mouse line recently reported by the Miano lab may be a valuable alternative. In this line, CreERT2 expression is driven by the Itga8 promoter, which shows preferential activity in vascular SMCs compared to visceral SMCs.21 This property can circumvent the risk of visceral smooth muscle phenotypes when studying vascular smooth muscle functions (Figure). However, this mouse line also carries some caveats. In contrast to the Myh11-CreERT2 transgenic lines, the Itga8-CreERT2 mouse is a knock-in line, in which the DNA construct encoding CreERT2 was inserted into the first exon of the Itga8 gene, which encodes the integrin a8 subunit. Because homozygosity for the Itga8 knock-in allele is lethal,21 haploinsufficiency may also be problematic. Although the authors provide data that one intact allele is sufficient to lead to normal ITGA8 protein levels in the aorta of healthy animals, this may not be the case in other vascular beds or under disease conditions. Another limitation of the Itga8-CreERT2 mouse line is recombinase activity in other cells, including hepatic stellate cells or glomerular cells of the kidney.21 In addition, Cre-mediated recombination in Itga8-CreERT2 mice is not entirely specific for vascular SMCs but also occurs, to some degree, in visceral SMCs, including in the urinary bladder and the uterus.21 This may still confound vascular phenotypes seen in conditional knockouts and, therefore, needs to be taken into consideration when using this line. Nevertheless, the thoroughly characterized Itga8-CreERT2 mouse line, which also expresses in both males and females,21 is likely to become the preferred tool for Cre/loxP-mediated recombination in vascular SMCs when confounding effects in visceral smooth muscle using Myh11-CreERT2 are anticipated or observed.Intraperitoneal tamoxifen injection is often used to induce recombination in CreERT2 constructs. Prior work from the Owens’ lab highlights another potential confounder in that the peanut oil vehicle was shown to cause autofluorescence in adipose-tissue macrophages,22 which could lead to mistaken identification of some macrophages as SMC-derived. Deaton et al17 circumvented this challenge by oral tamoxifen administration. In cases where shorter-term tamoxifen delivery is required, as in developmental studies, this caveat must be considered. Despite the limitations, the ability of these new Cre reagents to assess cardiovascular phenotypes in males and females, and–for Itga8-CreERT2–to avoid lethal visceral SMC complications, will lead to exciting new discoveries in vascular smooth muscle biology (Figure 1).Article InformationSources of FundingSupport was provided by awards from the National Institutes of Health (NIH) to B. J. O’Brien (T32HL007950) and K.A. Martin (R01HL151222, R01HL146101).Disclosures None.FootnotesFor Sources of Funding and Disclosures, see page 214.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to: Kathleen A. Martin, PhD, Yale Cardiovascular Research Center, 300 George St, Suite 759, New Haven, CT 06510. Email kathleen.[email protected]eduReferences1. Bennett MR, Sinha S, Owens GK. Vascular smooth muscle cells in atherosclerosis.Circ Res. 2016; 118:692–702. doi: 10.1161/circresaha.115.306361LinkGoogle Scholar2. Owens GK, Vernon SM, Madsen CS. Molecular regulation of smooth muscle cell differentiation.J Hypertens Suppl. 1996; 14:S55–S64. doi: 10.1152/physrev.00041.2003CrossrefMedlineGoogle Scholar3. Long JZ, Svensson KJ, Tsai L, Zeng X, Roh HC, Kong X, Rao RR, Lou J, Lokurkar I, Baur W, et al. A smooth muscle-like origin for beige adipocytes.Cell Metab. 2014; 19:810–820. doi: 10.1016/j.cmet.2014.03.025CrossrefMedlineGoogle Scholar4. Speer MY, Yang HY, Brabb T, Leaf E, Look A, Lin WL, Frutkin A, Dichek D, Giachelli CM. Smooth muscle cells give rise to osteochondrogenic precursors and chondrocytes in calcifying arteries.Circ Res. 2009; 104:733–741. doi: 10.1161/circresaha.108.183053LinkGoogle Scholar5. Miano JM, Fisher EA, Majesky MW. Fate and state of vascular smooth muscle cells in atherosclerosis.Circulation. 2021; 143:2110–2116. doi: 10.1161/circulationaha.120.049922LinkGoogle Scholar6. Nemenoff RA, Horita H, Ostriker AC, Furgeson SB, Simpson PA, VanPutten V, Crossno J, Offermanns S, Weiser-Evans MC. Sdf-1alpha induction in mature smooth muscle cells by inactivation of pten is a critical mediator of exacerbated injury-induced neointima formation.Arterioscler Thromb Vasc Biol. 2011; 31:1300–1308. doi: 10.1161/atvbaha.111.223701LinkGoogle Scholar7. Chappell J, Harman JL, Narasimhan VM, Yu H, Foote K, Simons BD, Bennett MR, Jorgensen HF. Extensive proliferation of a subset of differentiated, yet plastic, medial vascular smooth muscle cells contributes to neointimal formation in mouse injury and atherosclerosis models.Circ Res. 2016; 119:1313–1323. doi: 10.1161/CIRCRESAHA.116.309799LinkGoogle Scholar8. Espinosa-Diez C, Mandi V, Du M, Liu M, Gomez D. Smooth muscle cells in atherosclerosis: clones but not carbon copies.JVS Vasc Sci. 2021; 2:136–148.doi: 10.1016/j.jvssci.2021.02.002CrossrefMedlineGoogle Scholar9. Shankman LS, Gomez D, Cherepanova OA, Salmon M, Alencar GF, Haskins RM, Swiatlowska P, Newman AA, Greene ES, Straub AC, et al. Klf4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis.Nat Med. 2015; 21:628–63710.1038/nm.3866CrossrefMedlineGoogle Scholar10. Chakraborty R, Saddouk FZ, Carrao AC, Krause DS, Greif DM, Martin KA. Promoters to study vascular smooth muscle.Arterioscler Thromb Vasc Biol. 2019; 39:603–612. doi: 10.1161/atvbaha.119.312449LinkGoogle Scholar11. Wendling O, Bornert JM, Chambon P, Metzger D. Efficient temporally-controlled targeted mutagenesis in smooth muscle cells of the adult mouse.Genesis. 2009; 47:14–18. doi: 10.1002/dvg.20448CrossrefMedlineGoogle Scholar12. Sheikh AQ, Lighthouse JK, Greif DM. Recapitulation of developing artery muscularization in pulmonary hypertension.Cell Rep. 2014; 6:809–81710.1016/j.celrep.2014.01.042CrossrefMedlineGoogle Scholar13. Sheikh AQ, Misra A, Rosas IO, Adams RH, Greif DM. Smooth muscle cell progenitors are primed to muscularize in pulmonary hypertension.Sci Transl Med. 2015; 7:308ra159.10.1126/scitranslmed.aaa9712CrossrefMedlineGoogle Scholar14. Wirth A, Benyo Z, Lukasova M, Leutgeb B, Wettschureck N, Gorbey S, Orsy P, Horvath B, Maser-Gluth C, Greiner E, et al. G(12)-g(13)-larg-mediated signaling in vascular smooth muscle is required for salt-induced hypertension.Nat Med. 2008; 14:222–222.doi: 10.1038/nm1666CrossrefGoogle Scholar15. Miano JM, Cserjesi P, Ligon KL, Periasamy M, Olson EN. Smooth muscle myosin heavy chain exclusively marks the smooth muscle lineage during mouse embryogenesis.Circ Res. 1994; 75:803–812. doi: 10.1161/01.res.75.5.803LinkGoogle Scholar16. Madsen CS, Regan CP, Hungerford JE, White SL, Manabe I, Owens GK. Smooth muscle-specific expression of the smooth muscle myosin heavy chain gene in transgenic mice requires 5’-flanking and first intronic DNA sequence.Circ Res. 1998; 82:908–917. doi: 10.1161/01.res.82.8.908LinkGoogle Scholar17. Deaton RA, Bulut G, Serbulea V, Salamon A, Shankman LS, Tram Nguyen A, Owens GK. A new autosomal Myh11-CreERT2 smooth muscle cell lineage tracing and gene knockout mouse model—brief report.Arterioscler Thromb Vasc Biol. 2023; 43:203–211. doi: 10.1161/ATVBAHA.122.318160LinkGoogle Scholar18. Man JJ, Beckman JA, Jaffe IZ. Sex as a biological variable in atherosclerosis.Circ Res. 2020; 126:1297–1319. doi: 10.1161/circresaha.120.315930LinkGoogle Scholar19. Alvarez-Aznar A, Martinez-Corral I, Daubel N, Betsholtz C, Makinen T, Gaengel K. Tamoxifen-independent recombination of reporter genes limits lineage tracing and mosaic analysis using creer(t2) lines.Transgenic Res. 2020; 29:53–68. doi: 10.1007/s11248-019-00177-8CrossrefMedlineGoogle Scholar20. Rashbrook VS, Brash JT, Ruhrberg C. Cre toxicity in mouse models of cardiovascular physiology and disease.Nat Cardiovasc Res. 2022; 1:806–816. doi: 10.1038/s44161-022-00125-6CrossrefGoogle Scholar21. Warthi G, Faulkner JL, Doja J, Ghanam AR, Gao P, Yang AC, Slivano OJ, Barris CT, Kress TC, Zawieja SD, et al. Generation and comparative analysis of an itga8-creer (t2) mouse with preferential activity in vascular smooth muscle cells.Nat Cardiovasc Res. 2022; 1:1084–1100. doi: 10.1038/s44161-022-00162-1CrossrefMedlineGoogle Scholar22. Bulut GB, Alencar GF, Owsiany KM, Nguyen AT, Karnewar S, Haskins RM, Waller LK, Cherepanova OA, Deaton RA, Shankman LS, et al. Klf4 (kruppel-like factor 4)-dependent perivascular plasticity contributes to adipose tissue inflammation.Arterioscler Thromb Vasc Biol. 2021; 41:284–30110.1161/ATVBAHA.120.314703LinkGoogle Scholar23. Corliss BA, Ray HC, Mathews C, Fitzgerald K, Doty RW, Smolko CM, Shariff H, Peirce SM, Yates PA. Myh11 lineage corneal endothelial cells and ascs populate corneal endothelium.Invest Ophthalmol Vis Sci. 2019; 60:5095–5103. doi: 10.1167/iovs.19-27276CrossrefMedlineGoogle Scholar24. Hess DL, Kelly-Goss MR, Cherepanova OA, Nguyen AT, Baylis RA, Tkachenko S, Annex BH, Peirce SM, Owens GK. Perivascular cell-specific knockout of the stem cell pluripotency gene oct4 inhibits angiogenesis.Nat Commun. 2019; 10:96710.1038/s41467-019-08811-zCrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesA New Autosomal Myh11-CreERT2 Smooth Muscle Cell Lineage Tracing and Gene Knockout Mouse Model—Brief ReportRebecca A. Deaton, et al. Arteriosclerosis, Thrombosis, and Vascular Biology. 2023;43:203-211 February 2023Vol 43, Issue 2 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/ATVBAHA.122.318855PMID: 36601960 Originally publishedJanuary 5, 2023 Keywordsvascular diseasesmuscle, smoothEditorialsgenetic recombinationPDF download Advertisement" @default.
• W4313506721 created "2023-01-06" @default.
• W4313506721 creator A5061427544 @default.
• W4313506721 creator A5077470688 @default.
• W4313506721 creator A5089894090 @default.
• W4313506721 date "2023-02-01" @default.
• W4313506721 modified "2023-10-01" @default.
• W4313506721 title "“Cre”ating New Tools for Smooth Muscle Analysis" @default.
• W4313506721 cites W1997303582 @default.
• W4313506721 cites W1998486974 @default.
• W4313506721 cites W2019832656 @default.
• W4313506721 cites W2020346259 @default.
• W4313506721 cites W2045450215 @default.
• W4313506721 cites W2121192738 @default.
• W4313506721 cites W2121822802 @default.
• W4313506721 cites W2123740493 @default.
• W4313506721 cites W2124219264 @default.
• W4313506721 cites W2150949973 @default.
• W4313506721 cites W2180845934 @default.
• W4313506721 cites W2274924551 @default.
• W4313506721 cites W2419652918 @default.
• W4313506721 cites W2525459565 @default.
• W4313506721 cites W2911393219 @default.
• W4313506721 cites W2917673469 @default.
• W4313506721 cites W2981497325 @default.
• W4313506721 cites W2996061131 @default.
• W4313506721 cites W3018086681 @default.
• W4313506721 cites W3092905438 @default.
• W4313506721 cites W3103761932 @default.
• W4313506721 cites W3162482818 @default.
• W4313506721 cites W3164960363 @default.
• W4313506721 cites W4295138696 @default.
• W4313506721 cites W4308764911 @default.
• W4313506721 cites W4311586211 @default.
• W4313506721 doi "https://doi.org/10.1161/atvbaha.122.318855" @default.
• W4313506721 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/36601960" @default.
• W4313506721 hasPublicationYear "2023" @default.
• W4313506721 type Work @default.
• W4313506721 citedByCount "2" @default.
• W4313506721 countsByYear W43135067212023 @default.
• W4313506721 crossrefType "journal-article" @default.
• W4313506721 hasAuthorship W4313506721A5061427544 @default.
• W4313506721 hasAuthorship W4313506721A5077470688 @default.
• W4313506721 hasAuthorship W4313506721A5089894090 @default.
• W4313506721 hasBestOaLocation W43135067211 @default.
• W4313506721 hasConcept C41008148 @default.
• W4313506721 hasConcept C70721500 @default.
• W4313506721 hasConcept C86803240 @default.
• W4313506721 hasConceptScore W4313506721C41008148 @default.
• W4313506721 hasConceptScore W4313506721C70721500 @default.
• W4313506721 hasConceptScore W4313506721C86803240 @default.
• W4313506721 hasIssue "2" @default.
• W4313506721 hasLocation W43135067211 @default.
• W4313506721 hasLocation W43135067212 @default.
• W4313506721 hasOpenAccess W4313506721 @default.
• W4313506721 hasPrimaryLocation W43135067211 @default.
• W4313506721 hasRelatedWork W1641042124 @default.
• W4313506721 hasRelatedWork W1990804418 @default.
• W4313506721 hasRelatedWork W1993764875 @default.
• W4313506721 hasRelatedWork W2013243191 @default.
• W4313506721 hasRelatedWork W2046158694 @default.
• W4313506721 hasRelatedWork W2082860237 @default.
• W4313506721 hasRelatedWork W2130076355 @default.
• W4313506721 hasRelatedWork W2147794249 @default.
• W4313506721 hasRelatedWork W2748952813 @default.
• W4313506721 hasRelatedWork W2899084033 @default.
• W4313506721 hasVolume "43" @default.
• W4313506721 isParatext "false" @default.
• W4313506721 isRetracted "false" @default.
• W4313506721 workType "article" @default.