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Transforming growth factor-beta signaling via ALK1 and ALK5 regulates distinct functional pathways in vein graft intimal hyperplasia

EL Low, JT Schwartze, A Kurkiewicz, M Pek, DJ Kelly, AS Shaw, M Thorikay, J McClure, M McBride, S Arias-Rivas, SE Francis, NW Morrell, C Delles, P Herzyk, MJ Havenga, SA Nicklin, P Ten Dijke, AH Baker, AC Bradshaw
doi: https://doi.org/10.1101/860320
EL Low
1Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
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JT Schwartze
1Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
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A Kurkiewicz
1Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
2Biomage, Level 5, Sir Alwyn Williams Building, University of Glasgow, Glasgow, UK
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M Pek
2Biomage, Level 5, Sir Alwyn Williams Building, University of Glasgow, Glasgow, UK
3School of Computing Science, University of Glasgow, Glasgow, UK
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DJ Kelly
1Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
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AS Shaw
1Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
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M Thorikay
4Dept. Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
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J McClure
1Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
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M McBride
1Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
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S Arias-Rivas
5Batavia Biosciences B.V, Leiden, The Netherlands
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SE Francis
6Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield Medical School, Beech Hill Road, Sheffield, UK
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NW Morrell
7Department of Medicine, University of Cambridge, School of Clinical Medicine, Cambridge, UK
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C Delles
1Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
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P Herzyk
8Glasgow Polyomics, University of Glasgow, Switchback Road, Bearsden, Glasgow, UK
9Institute of Molecular, Cell and Systems Biology, University of Glasgow, Glasgow, UK
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MJ Havenga
5Batavia Biosciences B.V, Leiden, The Netherlands
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SA Nicklin
1Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
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P Ten Dijke
4Dept. Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
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AH Baker
10Centre for Cardiovascular Sciences, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
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AC Bradshaw
1Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
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  • For correspondence: Angela.Bradshaw@glasgow.ac.uk
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Abstract

Rationale Transforming growth factor-beta (TGFβ) is tightly regulated at multiple levels, with regulation at the receptor level now recognized as a key determinant of the cellular response to this pleiotropic cytokine. TGFβ promotes saphenous vein graft neointima formation after coronary artery bypass graft (CABG) surgery, inducing smooth muscle cell (SMC) hyperplasia and fibrosis by signaling via activin receptor-like kinase 5(ALK5). However, the role of the alternate TGFβ receptor ALK1 remains completely unknown.

Objective To define the receptor pathways activated by TGFβ in SMCs and their mechanistic importance during CABG neointima formation.

Methods and results Radioligand co-IP assays revealed direct interactions between TGFβ, ALK5 and ALK1 in primary saphenous vein graft SMC (HSVSMC) from patients undergoing CABG. Knockdown and pharmacological inhibition of ALK5 or ALK1 in HSVSMC significantly attenuated TGFβ-induced phosphorylation of receptor-regulated (R)-Smads 2/3 and 1/5, respectively. Microarray profiling followed by qRT-PCR validation showed that TGFβ induced distinct transcriptional networks downstream of ALK5 or ALK1, associated with HSVSMC contractility and migration, respectively and confirmed using migration assays as well as qRT-PCR and western blot assays of contractile SMC markers. scRNAseq analysis of TGFβ-treated HSVSMC identified distinct subgroups of cells showing ALK5 or ALK1 transcriptional responses, while RNA velocity analyses indicated divergence in differentiation towards ALK5 or ALK1-dominant lineages. ALK1, ALK5 and their downstream effectors pSmad1/5 and pSmad2/3 were localized to αSMA+ neointimal SMCs in remodelled mouse vein grafts. Pharmacological inhibition or genetic ablation of Smad1/5 substantially reducing neointima formation following acute vascular injury. Notably, expression and activation of ALK1, ALK5 and their respective downstream R-Smads was already evident in hyperplastic saphenous veins prior to grafting.

Conclusions Whilst canonical TGFβ signaling via ALK5 promotes a contractile HSVSMC phenotype, transactivation of ALK1 by TGFβ induces neointima formation by driving cell migration. Restoring the balance between ALK1 and ALK5 in HSVSMC may represent a novel therapeutic strategy for vein graft failure.

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Posted November 29, 2019.
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Transforming growth factor-beta signaling via ALK1 and ALK5 regulates distinct functional pathways in vein graft intimal hyperplasia
EL Low, JT Schwartze, A Kurkiewicz, M Pek, DJ Kelly, AS Shaw, M Thorikay, J McClure, M McBride, S Arias-Rivas, SE Francis, NW Morrell, C Delles, P Herzyk, MJ Havenga, SA Nicklin, P Ten Dijke, AH Baker, AC Bradshaw
bioRxiv 860320; doi: https://doi.org/10.1101/860320
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Transforming growth factor-beta signaling via ALK1 and ALK5 regulates distinct functional pathways in vein graft intimal hyperplasia
EL Low, JT Schwartze, A Kurkiewicz, M Pek, DJ Kelly, AS Shaw, M Thorikay, J McClure, M McBride, S Arias-Rivas, SE Francis, NW Morrell, C Delles, P Herzyk, MJ Havenga, SA Nicklin, P Ten Dijke, AH Baker, AC Bradshaw
bioRxiv 860320; doi: https://doi.org/10.1101/860320

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