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Smooth muscle αv integrins regulate vascular fibrosis via CD109 downregulation of TGF-β signalling

Authors :
Zhenlin Li
Ekaterina Belozertseva
Ara Parlakian
Rümeyza Bascetin
Huguette Louis
Yuki Kawamura
Jocelyne Blanc
Jacqueline Gao-Li
Florence Pinet
Adam Lacy-Hulbert
Pascal Challande
Jay D Humphrey
Veronique Regnault
Patrick Lacolley
Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A)
Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS)
Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Défaillance Cardiovasculaire Aiguë et Chronique (DCAC)
Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)
Yale University [New Haven]
Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE)
Institut Pasteur de Lille
Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)
University of Washington [Seattle]
Institut Jean Le Rond d'Alembert (DALEMBERT)
Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015)
ANR-13-BSV1-0026,EVASION,Intégrines alphav des cellules musculaires lisses vasculaires : liens mécanistiques entre rigidité artérielle et génération de thrombine intrapariétale(2013)
Source :
European Heart Journal Open, European Heart Journal Open, 2023, 3 (2), pp.oead010. ⟨10.1093/ehjopen/oead010⟩
Publication Year :
2023
Publisher :
Oxford University Press (OUP), 2023.

Abstract

Aimsαv integrins are implicated in fibrosis in a number of organs through their ability to activate TGF-β. However their role in vascular fibrosis and collagen accumulation is only partially understood. Here we have used αv conditional knockout mice and cell lines to determine how αv contributes to vascular smooth muscle cell (VSMC) function in vascular fibrosis and the role of TGF-β in that process.Methods and resultsAngiotensin II (Ang II) treatment causes upregulation of αv and β3 expression in the vessel wall, associated with increased collagen deposition. We found that deletion of αv integrin subunit from VSMCs (αvSMKO) protected mice against angiotensin II-induced collagen production and assembly. Transcriptomic analysis of the vessel wall in αvSMKO mice and controls identified a significant reduction in expression of fibrosis and related genes in αvSMKO mice. In contrast, αvSMKO mice showed prolonged expression of CD109, which is known to affect TGF-β signalling. Using cultured mouse and human VSMCs, we showed that overexpression of CD109 phenocopied knockdown of αv integrin, attenuating collagen expression, TGF-β activation, and Smad2/3 signalling in response to angiotensin II or TGF-β stimulation. CD109 and TGF-β receptor were internalized in early endosomes.ConclusionWe identify a role for VSMC αv integrin in vascular fibrosis and show that αv acts in concert with CD109 to regulate TGF-β signalling.

Details

ISSN :
27524191
Volume :
3
Database :
OpenAIRE
Journal :
European Heart Journal Open
Accession number :
edsair.doi.dedup.....b0e2bded1db1bc8b7de858b95e6a58de