Vascularization 2 PDF

Molecular insights into arteriovenous malformations ANAT416_W2024 / March 28th 2024 Alexandre Dubrac Anatomy and Cell Biology Dept. / Human Genetics Dept. / McGill University [email protected] Associate professor Dépt. de Pathologie et Biologie Cellulaire / Dépt. d’ophtalmologie / Universit...

Molecular insights into arteriovenous malformations ANAT416_W2024 / March 28th 2024 Alexandre Dubrac Anatomy and Cell Biology Dept. / Human Genetics Dept. / McGill University [email protected] Associate professor Dépt. de Pathologie et Biologie Cellulaire / Dépt. d’ophtalmologie / Université de Montréal [email protected] The anatomy of the vascular system Systemic circulation Pulmonary circulation Artery =They transport oxygenated blood to the tissues and organs. Vein=They transport deoxygenated blood to the right heart. Artery = They transport deoxygenated blood to the lungs (alveoli). Vein = They transport oxygenated blood to the left heart. Between artery and vein= Capillaries Site of gas exchange. Brain neurovascular patterning A B C D B C D Arachnoid mater Subarachnoid space (SAS) Pia mater Perivascular space © EMBO Perivascular fibroblasts Arterial SMC Pericytes Artery Venous SMC Capillaries Vein Arteriolar SMC Astrocyte aSMC pericyte Capillary Artery Perivascular macrophage vSMC Vein Lendahl U.. et al EMBO reports, 2019 PVF SMC PVF SMC EC 14693178, 2019, 11, Downloaded from https://www.embopress.org/doi/10.15252/embr.201948070 by Universite De Montreal (Pavillon Roger-Gaudry), Wiley Online Library on [26/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Onlin EMBO reports Urban Lendahl et al Intima Media Intima: Endothelial cells (EC) Adventitia Media: Smooth muscle cells (SMC) Adventitia: connective tissue and collagen/elastic fibers EMBO reports A B C D B C D Arachnoid mater Subarachnoid space (SAS) Pia mater Perivascular space © EMBO Perivascular fibroblasts Arterial SMC Pericytes Artery Venous SMC Capillaries Vein Arteriolar SMC Astrocyte aSMC SMA+ vSMC SMA- Capillary Artery Perivascular macrophage Vein PVF SMC EC BM BM PC AEF BM EC SMC PVF 14693178, 2019, 11, Downloaded from https://www.embopress.org/doi/10.15252/embr.201948070 by Universite De Montreal (Pavillon Roger-Gaudry), Wiley Online Library on [26/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of Retina vascular remodeling Urban Lendahl et al Brain neurovascular patterning P12 mouse brain (lightsheet) αSMA = aSMC P12 mouse brain surface CD31 = EC αSMA = aSMC A V 200µm 200µm Collaboration: Frederic Lesage Polytechnic/ICM Montreal Retina vascular remodeling Flow-induced Artery formation Yuki Sato et al plos one 2010 Lee HW. et al EMM 2022 Flow-induced arterial-venous differentiation relies on endothelial cell plasticity Vein New Artery (15h) Artery Ligation/clamp Le Noble F. et al Development 2004 Flow-induced EC arterialization Arterial specification Trimm E. Red-Horse K. Nat. Reviews Cardiology 2022 Mouse brain EC arteriovenous identity UMAP 2 Arterial ECs UMAP 1 Venous ECs Flow marker Arterial marker Venous marker Notch signaling is essential A-V specification Gridley T. Development 2007 ; Curr Top Dev Biol. 2013 Pitulescu M.E. et al Nat Cell Biol 2017 Fang J.S. Nat Communications 2017 Tip-cells contribute to artery formation (Notch signaling) Xu C. et al Nat. Communications 2014 Flow-induced EC arterialization Arterial specification Arterial ECs do not proliferate Trimm E. Red-Horse K. Nat. Reviews Cardiology 2022 Artery formation Lineage tracing with venous endothelial cells CRE-driver Mouse retina Mouse adult brain Lee et al, Circulation, 2021 Flow-induced EC arterialization Arterial specification Media layer formation SMC recruitment and specification Trimm E. Red-Horse K. Nat. Reviews Cardiology 2022 Notch signaling promotes SMC recruitment Notch inhibition Fang J.S. Nat Communications 2017 Arteriovenous differentiation defects: AVM (arteriovenous malformation) Notch Vein Capillary Artery AVMs: Loss of capillary transition and hemodynamic changes Endothelial defects: Loss of arteriovenous markers Hyperproliferation Increase of cell size Hereditary Hemorrhagic Telangiectasia (HHT) Hereditary Hemorrhagic Telangiectasia (HHT) = HHT5 Rendu-Weber-Osler disease Inherited autosomal dominant disorder - Prevalence : 1:5000 individuals - Nosebleeds - Telangiectasia : Vessel dilatation on the lips, tongue, fingers and nasal, buccal and gastrointestinal mucosa HHT2 - Arteriovenous malformations (AVM) in lung, liver and brain Telangiectasia : HHT patient with brain AVM (bAVM) : HHT1 JP-HHT Drapé et al, Frontiers in Human Neuroscience 2022 bAVM molecular signature and mechanisms remain unclear Genes mutation 2nd hit Progression during life Development Diagnostic Normal vasculature Early-stage bAVM Consequences and symptoms Neurological troubles : Headache or epileptic seizure Risk of rupture : Cerebral haemorrhage Asymptomatic for long periods Late-stage bAVM Limited therapeutic possibilities Surgical resection Endovascular embolization Stereotactic radiosurgery Mohr et al, Curr Neurol Neurosci, 2013 HHT AVM models Ola R. et al Nat Comm 2016 Ola R. et al Circulation 2018 Drapé et al, Frontiers in Human Neuroscience 2022 HHT AVM models Ola R. et al Nat Comm 2016 Supplementary Figure 1. Blocking BMP9/10-Alk1 signalling induces vascular malforma Ola R. et al Circulation 2018 a, Schematic of the experimental strategy to assess Alk1 deletion or BMP9/10 blockade. Arrow Drapé et al, Frontiers in Human Neuroscience 2022 HHT AVM models Overexpression of Activin Receptor-Like Kinase 1 in Endothelial Cells Suppresses Development of Arteriovenous Malformations in Mouse Models of Hereditary Hemorrhagic Telangiectasia Downloaded from http://ahajournals.org b Kim Y.H.. et al Circ Research 2020 Drapé et al, Frontiers in Human Neuroscience 2022 AVM exhibits A-V identity defects Supplementary Figure 2. Characterization of vascular malformations in mouse retinas. a, Cell cycle analysis of retinal endothelial cells with the indicated genotypes. n=16-18 retinas pe bars: S.E.M, ns- nonsignificant, *P