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This study was supported by the Fondo de Investigacion Sanitaria del Instituto de Salud Carlos III (PI16/188, PI19/855), the European Regional Development Fund, and the European Commission through H2020-EU.1.1, European Research Council grant ERC-2016-StG 715322-EndoMitTalk, and Gobierno de Espana SAF2016-80305P. This work was partially supported by Comunidad de Madrid (S2017/BMD 3867 RENIM-CM) and cofinanced by the European Structural and Investment Fund. M.M. is supported by the Miguel Servet Program (CP 19/014, Fundacion de Investigacion del Hospital 12 de Octubre). J.O., E.G., and R.R-D. are supported by Juan de la Cierva (FJCI2017-33855, IJC2018-036850-I, and IJCI-2017-31399, respectively). Support was also provided by Ministerio de Ciencia e Innovacion grants (RTI2018-099246-B-I00 to J.M.R. and PI18/00543 to J.F.N.) and Comunidad de Madrid and Fondo Social Europeo funds (AORTASANA-CM; B2017/BMD-3676 to A.M.B., A.F., and J.M.R.). J.M.R. was also funded by Fundacion La Caixa (HR18-00068) and the Marfan Foundation (USA). J.M.R. and J.L.M.V. were also funded by Centro de Investigacion Biomedica en Red Enfermedades Cardiovasculares of Ministerio de Ciencia e Innovacion (CB16/11/00264). J.F.N. was funded by Ministerio de Economia y Competitividad (PI18/00543) and Centro de Investigacion Biomedica en Red Enfermedades Cardiovasculares (CB16/11/00264), and was cofunded by Fondo Europeo de Desarrollo Regional.

Analysis of institutional authors

Forteza Gil, Alberto PabloAuthorOller, JorgeAuthorGabande-Rodriguez, EnriqueAuthorRodrigues-Diez, RaquelAuthorMartin-Ventura, Jose LuisAuthorBriones, Ana MAuthorMittelbrunn, MariaCorresponding Author
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Article

Extracellular Tuning of Mitochondrial Respiration Leads to Aortic Aneurysm

Publicated to:CIRCULATION. 143 (21): 2091-2109 - 2021-05-25 143(21), DOI: 10.1161/CIRCULATIONAHA.120.051171

Authors: Oller, Jorge; Gabande-Rodriguez, Enrique; Ruiz-Rodriguez, Maria Jesus; Desdin-Mico, Gabriela; Aranda, Juan Francisco; Rodrigues-Diez, Raquel; Ballesteros-Martinez, Constanza; Blanco, Eva Maria; Roldan-Montero, Raquel; Acuna, Pedro; Nistal, J Francisco; Lino Cardenas, Christian L; Lindsay, Mark Evan; Martin-Ventura, Jose Luis; Briones, Ana M; Miguel Redondo, Juan; Mittelbrunn, Maria

Affiliations

Consejo Super Invest Cient Univ Autonoma Madrid, Dept Biol Mol, Ctr Biol Mol Severo Ochoa, Madrid, Spain - Author
Ctr Invest Biomed Red Enfermedades Cardiovasc, Madrid, Spain - Author
Ctr Nacl Invest Cardiovasc Carlos III, Madrid, Spain - Author
Fdn Jimenez Diaz, Inst Invest Sanitaria, Madrid, Spain - Author
Hosp Univ Puerta Hierro, Madrid, Spain - Author
Inst Invest Sanitaria Hosp 12 Octubre i 12, Madrid, Spain - Author
Massachusetts Gen Hosp, Thorac Aort Ctr, Boston, MA 02114 USA - Author
Univ Autonoma Madrid, Inst Invest Hosp La Paz, Dept Farmacol, Madrid, Spain - Author
Univ Cantabria, Hosp Univ Marques Valdecilla, Cardiovasc Surg, IDIVAL, Santander, Spain - Author
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Abstract

Background: Marfan syndrome (MFS) is an autosomal dominant disorder of the connective tissue caused by mutations in the FBN1 (fibrillin-1) gene encoding a large glycoprotein in the extracellular matrix called fibrillin-1. The major complication of this connective disorder is the risk to develop thoracic aortic aneurysm. To date, no effective pharmacologic therapies have been identified for the management of thoracic aortic disease and the only options capable of preventing aneurysm rupture are endovascular repair or open surgery. Here, we have studied the role of mitochondrial dysfunction in the progression of thoracic aortic aneurysm and mitochondrial boosting strategies as a potential treatment to managing aortic aneurysms. Methods: Combining transcriptomics and metabolic analysis of aortas from an MFS mouse model (Fbn1(c1039g/+)) and MFS patients, we have identified mitochondrial dysfunction alongside with mtDNA depletion as a new hallmark of aortic aneurysm disease in MFS. To demonstrate the importance of mitochondrial decline in the development of aneurysms, we generated a conditional mouse model with mitochondrial dysfunction specifically in vascular smooth muscle cells (VSMC) by conditional depleting Tfam (mitochondrial transcription factor A; Myh11-Cre(ERT2)Tfam(flox/flox) mice). We used a mouse model of MFS to test for drugs that can revert aortic disease by enhancing Tfam levels and mitochondrial respiration. Results: The main canonical pathways highlighted in the transcriptomic analysis in aortas from Fbn1(c1039g/+) mice were those related to metabolic function, such as mitochondrial dysfunction. Mitochondrial complexes, whose transcription depends on Tfam and mitochondrial DNA content, were reduced in aortas from young Fbn1(c1039g/+) mice. In vitro experiments in Fbn1-silenced VSMCs presented increased lactate production and decreased oxygen consumption. Similar results were found in MFS patients. VSMCs seeded in matrices produced by Fbn1-deficient VSMCs undergo mitochondrial dysfunction. Conditional Tfam-deficient VSMC mice lose their contractile capacity, showed aortic aneurysms, and died prematurely. Restoring mitochondrial metabolism with the NAD precursor nicotinamide riboside rapidly reverses aortic aneurysm in Fbn1(c1039g/+) mice. Conclusions: Mitochondrial function of VSMCs is controlled by the extracellular matrix and drives the development of aortic aneurysm in Marfan syndrome. Targeting vascular metabolism is a new available therapeutic strategy for managing aortic aneurysms associated with genetic disorders.

Keywords
AnimalsAortic aneurysmCellsDegeneratioDisease models, animalDnaDna, mitochondrialExtracellular matrixGenetic diseasesGenetic diseases, inbornGeneticsGlycolysisHumansInbornLosartanMarfan syndromeMarfan-syndromeMechanotransductionMetabolismMiceMitochondriaMitochondrialMouse modelMuscleMuscle, smooth, vascularNad(+) deficiencySmoothVasculaVascular smooth-muscle

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal CIRCULATION due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2021, it was in position 2/143, thus managing to position itself as a Q1 (Primer Cuartil), in the category Peripheral Vascular Disease. Notably, the journal is positioned above the 90th percentile.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 7.6. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Weighted Average of Normalized Impact by the Scopus agency: 8.97 (source consulted: FECYT Feb 2024)
  • Field Citation Ratio (FCR) from Dimensions: 36.34 (source consulted: Dimensions May 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-05-13, the following number of citations:

  • WoS: 64
  • Scopus: 78
  • Europe PMC: 44
  • OpenCitations: 68
Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-05-13:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 90.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 90 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 62.05.
  • The number of mentions on the social network Facebook: 1 (Altmetric).
  • The number of mentions on the social network X (formerly Twitter): 104 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.
Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: United States of America.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (OLLER PEDROSA, JORGE) and Last Author (MITTELBRUNN HERRERO, MARIA).

the author responsible for correspondence tasks has been MITTELBRUNN HERRERO, MARIA.