A non-genetic model of vascular shunts informs on the cellular mechanisms of formation and resolution of arteriovenous malformations.

Autor:	Ouarné M; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon 1649-028, Portugal., Pena A; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon 1649-028, Portugal.; Católica Biomedical Research Centre, Universidade Católica Portuguesa, Católica Medical School, Lisbon 1649-023, Portugal., Ramalho D; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon 1649-028, Portugal.; Católica Biomedical Research Centre, Universidade Católica Portuguesa, Católica Medical School, Lisbon 1649-023, Portugal., Conchinha NV; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon 1649-028, Portugal., Costa T; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon 1649-028, Portugal., Enjalbert R; Centre for Medical Informatics, Usher Institute, The University of Edinburgh, Edinburgh EH16 4UX, UK., Figueiredo AM; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon 1649-028, Portugal., Saraiva MP; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon 1649-028, Portugal., Carvalho Y; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon 1649-028, Portugal., Bernabeu MO; Centre for Medical Informatics, Usher Institute, The University of Edinburgh, Edinburgh EH16 4UX, UK.; The Bayes Centre, The University of Edinburgh, Edinburgh EH8 9BT, UK., Henao Misikova L; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon 1649-028, Portugal.; Católica Biomedical Research Centre, Universidade Católica Portuguesa, Católica Medical School, Lisbon 1649-023, Portugal., Oh SP; Barrow Aneurysm & AVM Research Center, Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ 85013, USA., Franco CA; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon 1649-028, Portugal.; Católica Biomedical Research Centre, Universidade Católica Portuguesa, Católica Medical School, Lisbon 1649-023, Portugal.
Jazyk:	angličtina
Zdroj:	Cardiovascular research [Cardiovasc Res] 2024 Dec 04; Vol. 120 (15), pp. 1967-1984.
DOI:	10.1093/cvr/cvae160
Abstrakt:	Aims: Arteriovenous malformations (AVMs), a disorder characterized by direct shunts between arteries and veins, are associated with genetic mutations. However, the mechanisms leading to AV shunt formation and how shunts can be reverted are poorly understood. Methods and Results: Here, we report that oxygen-induced retinopathy (OIR) protocol leads to the consistent and stereotypical formation of AV shunts in non-genetically altered mice. OIR-induced AV shunts show all the canonical markers of AVMs. Genetic and pharmacological interventions demonstrated that changes in the volume of venous endothelial cells (EC)-hypertrophic venous cells-are the initiating step promoting AV shunt formation, whilst EC proliferation or migration played minor roles. Inhibition of the mTOR pathway prevents pathological increases in EC volume and significantly reduces the formation of AV shunts. Importantly, we demonstrate that ALK1 signalling cell-autonomously regulates EC volume in pro-angiogenic conditions, establishing a link with hereditary haemorrhagic telangiectasia-related AVMs. Finally, we demonstrate that a combination of EC volume control and EC migration is associated with the regression of AV shunts. Conclusion: Our findings highlight that an increase in the EC volume is the key mechanism driving the initial stages of AV shunt formation, leading to asymmetric capillary diameters. Based on our results, we propose a coherent and unifying timeline leading to the fast conversion of a capillary vessel into an AV shunt. Our data advocate for further investigation into the mechanisms regulating EC volume in health and disease as a way to identify therapeutic approaches to prevent and revert AVMs. Competing Interests: Conflict of interest: none declared. (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)
Databáze:	MEDLINE
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