Role of PATJ in stroke prognosis by modulating endothelial to mesenchymal transition through the Hippo/Notch/PI3K axis

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  • dc.contributor.author Medina Dols, Aina
  • dc.contributor.author Mola Caminal, Marina
  • dc.contributor.author Soriano Tarraga, Carolina
  • dc.contributor.author Giralt-Steinhauer, Eva
  • dc.contributor.author Lazcano Dobao, Uxue
  • dc.contributor.author Fernández-Pérez, Isabel
  • dc.contributor.author Jiménez-Balado, Joan
  • dc.contributor.author Jiménez Conde, Jordi
  • dc.contributor.author Vives Bauzá, Cristòfol
  • dc.date.accessioned 2024-10-08T06:26:26Z
  • dc.date.available 2024-10-08T06:26:26Z
  • dc.date.issued 2024
  • dc.description.abstract Through GWAS studies we identified PATJ associated with functional outcome after ischemic stroke (IS). The aim of this study was to determine PATJ role in brain endothelial cells (ECs) in the context of stroke outcome. PATJ expression analyses in patient's blood revealed that: (i) the risk allele of rs76221407 induces higher expression of PATJ, (ii) PATJ is downregulated 24 h after IS, and (iii) its expression is significantly lower in those patients with functional independence, measured at 3 months with the modified Rankin scale ((mRS) ≤2), compared to those patients with marked disability (mRS = 4-5). In mice brains, PATJ was also downregulated in the injured hemisphere at 48 h after ischemia. Oxygen-glucose deprivation and hypoxia-dependent of Hypoxia Inducible Factor-1α also caused PATJ depletion in ECs. To study the effects of PATJ downregulation, we generated PATJ-knockdown human microvascular ECs. Their transcriptomic profile evidenced a complex cell reprogramming involving Notch, TGF-ß, PI3K/Akt, and Hippo signaling that translates in morphological and functional changes compatible with endothelial to mesenchymal transition (EndMT). PATJ depletion caused loss of cell-cell adhesion, upregulation of metalloproteases, actin cytoskeleton remodeling, cytoplasmic accumulation of the signal transducer C-terminal transmembrane Mucin 1 (MUC1-C) and downregulation of Notch and Hippo signaling. The EndMT phenotype of PATJ-depleted cells was associated with the nuclear recruitment of MUC1-C, YAP/TAZ, β-catenin, and ZEB1. Our results suggest that PATJ downregulation 24 h after IS promotes EndMT, an initial step prior to secondary activation of a pro-angiogenic program. This effect is associated with functional independence suggesting that activation of EndMT shortly after stroke onset is beneficial for stroke recovery.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Medina-Dols A, Cañellas G, Capó T, Solé M, Mola-Caminal M, Cullell N, et al. Role of PATJ in stroke prognosis by modulating endothelial to mesenchymal transition through the Hippo/Notch/PI3K axis. Cell Death Discov. 2024 Feb 17;10(1):85. DOI: 10.1038/s41420-024-01857-z
  • dc.identifier.doi http://dx.doi.org/10.1038/s41420-024-01857-z
  • dc.identifier.issn 2058-7716
  • dc.identifier.uri http://hdl.handle.net/10230/61344
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Cell Death Discov. 2024 Feb 17;10(1):85
  • dc.rights © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Blood–brain barrier
  • dc.subject.keyword Epithelial–mesenchymal transition
  • dc.subject.keyword Mechanisms of disease
  • dc.title Role of PATJ in stroke prognosis by modulating endothelial to mesenchymal transition through the Hippo/Notch/PI3K axis
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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