Cardiac pericyte reprogramming by MEK inhibition promotes arteriologenesis and angiogenesis of the ischemic heart

Elisa Avolio; Rajesh G Katare; Anita C Thomas; Andrea Caporali; Daryl Schwenke; Michele Carrabba; Marco Meloni; Massimo Caputo; Paolo R Madeddu

doi:10.1172/JCI152308

Cardiac pericyte reprogramming by MEK inhibition promotes arteriologenesis and angiogenesis of the ischemic heart

Elisa Avolio, Rajesh G Katare, Anita C Thomas, Andrea Caporali, Daryl Schwenke, Michele Carrabba, Marco Meloni, Massimo Caputo, Paolo R Madeddu

Research output: Contribution to journal › Article (Academic Journal) › peer-review

27 Citations (Scopus)

86 Downloads (Pure)

Abstract

Pericytes (PC) are abundant yet remain the most enigmatic and ill-defined cell population in the heart. Here, we investigated if PC can be reprogrammed to aid neovascularization. Primary PC from human and mouse hearts acquired cytoskeleton proteins typical of vascular smooth muscle cells (VSMC) upon exclusion of EGF/bFGF, which signal through ERK1/2, or exposure to the MEK-inhibitor PD0325901. Differentiated PC became more proangiogenic, more responsive to vasoactive agents, and insensitive to chemoattractants. RNA-Sequencing revealed transcripts marking the PD0325901-induced transition into proangiogenic, stationary VSMC-like cells, including the unique expression of two angiogenesis-related markers, aquaporin 1 (AQP1) and cellular retinoic acid-binding protein 2 (CRABP2), which were further verified at the protein level. This enabled us to trace PC during in vivo studies. In mice, implantation of Matrigel plugs containing human PC+PD0325901 promoted the formation of α-SMApos neovessels compared with PC only. Two-week oral administration of PD0325901 to mice increased the heart arteriolar density, total vascular area, arteriole coverage by PDGFRβposAQP1posCRABP2pos PC, and myocardial perfusion. Short-duration PD0325901 treatment of mice after myocardial infarction enhanced the peri-infarct vascularization, reduced the scar, and improved systolic function. In conclusion, myocardial PC have intrinsic plasticity that can be pharmacologically modulated to promote reparative vascularization of the ischemic heart.

Original language	English
Article number	e152308
Pages (from-to)	1-17
Journal	Journal of Clinical Investigation
Volume	132
Issue number	10
Early online date	26 Mar 2022
DOIs	https://doi.org/10.1172/JCI152308
Publication status	Published - 16 May 2022

Bibliographical note

Funding Information:
We wish to acknowledge the Wolfson Bioimaging Facility, University of Bristol, for the access to confocal microscopes and expert technical advice. We also acknowledge the University of Edinburgh Bioresearch & Veterinary Services at the Little France Facility for supporting the in vivo Matrigel experiment. Drawings were created with BioRender.com. This work was funded by the British Heart Foundation Centre for Regenerative Medicine Award (II) - “Centre for Vascular Regeneration” (RM/17/3/33381) to PM (co-lead of Work Package 3). In addition, it was supported by a grant from the National Institute for Health Research (NIHR) Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. EA was a Research Associate supported by the British Heart Foundation. M Caputo is a British Heart Foundation Professor of Cardiac Surgery.

Publisher Copyright:
© 2022, Avolio et al.

Research Groups and Themes

Bristol Heart Institute

Keywords

pericytes
arteriologenesis
MEK inhibitor
myocardial ischemia
angiogenesis

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10.1172/JCI152308

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27 Citations
3 Conference Abstract
1 Other contribution

Transcriptomics signature of human heart vascular pericytes - Expression profiling by high throughput sequencing (Accession number GSE195917)
Avolio, E. & Madeddu, P. R., 29 Mar 2022
Research output: Other contribution
Cardiac pericytes can be pharmacologically redirected towards a smooth muscle phenotype to enhance the revascularisation of the ischemic heart
Avolio, E., Katare, R. G., Thomas, A. C., Caporali, A., Schwenke, D., Meloni, M., Caputo, M. & Madeddu, P. R., 15 Feb 2021, (Unpublished) p. 13. 1 p.
Research output: Contribution to conference › Conference Abstract › peer-review

File
A short term treatment with a Mek1/2 inhibitor promotes myocardial arteriogenesis and perfusion in vivo: focus on cardiac mural cells
Avolio, E., Thomas, A. C., Caporali, A., Meloni, M., Caputo, M. & Madeddu, P. R., 25 Nov 2020. 1 p.
Research output: Contribution to conference › Conference Abstract › peer-review

Open Access
File
49 Downloads (Pure)

BHF Reflections of Research Science Image competition
Avolio, E. (Recipient), 25 Aug 2021
Prize: Prizes, Medals, Awards and Grants
Young Investigator Award in Vascular Biology
Avolio, E. (Recipient), Aug 2020
Prize: Prizes, Medals, Awards and Grants

Cite this

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title = "Cardiac pericyte reprogramming by MEK inhibition promotes arteriologenesis and angiogenesis of the ischemic heart",

abstract = "Pericytes (PC) are abundant yet remain the most enigmatic and ill-defined cell population in the heart. Here, we investigated if PC can be reprogrammed to aid neovascularization. Primary PC from human and mouse hearts acquired cytoskeleton proteins typical of vascular smooth muscle cells (VSMC) upon exclusion of EGF/bFGF, which signal through ERK1/2, or exposure to the MEK-inhibitor PD0325901. Differentiated PC became more proangiogenic, more responsive to vasoactive agents, and insensitive to chemoattractants. RNA-Sequencing revealed transcripts marking the PD0325901-induced transition into proangiogenic, stationary VSMC-like cells, including the unique expression of two angiogenesis-related markers, aquaporin 1 (AQP1) and cellular retinoic acid-binding protein 2 (CRABP2), which were further verified at the protein level. This enabled us to trace PC during in vivo studies. In mice, implantation of Matrigel plugs containing human PC+PD0325901 promoted the formation of α-SMApos neovessels compared with PC only. Two-week oral administration of PD0325901 to mice increased the heart arteriolar density, total vascular area, arteriole coverage by PDGFRβposAQP1posCRABP2pos PC, and myocardial perfusion. Short-duration PD0325901 treatment of mice after myocardial infarction enhanced the peri-infarct vascularization, reduced the scar, and improved systolic function. In conclusion, myocardial PC have intrinsic plasticity that can be pharmacologically modulated to promote reparative vascularization of the ischemic heart.",

keywords = "pericytes, arteriologenesis, MEK inhibitor, myocardial ischemia, angiogenesis",

author = "Elisa Avolio and Katare, {Rajesh G} and Thomas, {Anita C} and Andrea Caporali and Daryl Schwenke and Michele Carrabba and Marco Meloni and Massimo Caputo and Madeddu, {Paolo R}",

note = "Funding Information: We wish to acknowledge the Wolfson Bioimaging Facility, University of Bristol, for the access to confocal microscopes and expert technical advice. We also acknowledge the University of Edinburgh Bioresearch & Veterinary Services at the Little France Facility for supporting the in vivo Matrigel experiment. Drawings were created with BioRender.com. This work was funded by the British Heart Foundation Centre for Regenerative Medicine Award (II) - “Centre for Vascular Regeneration” (RM/17/3/33381) to PM (co-lead of Work Package 3). In addition, it was supported by a grant from the National Institute for Health Research (NIHR) Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. EA was a Research Associate supported by the British Heart Foundation. M Caputo is a British Heart Foundation Professor of Cardiac Surgery. Publisher Copyright: {\textcopyright} 2022, Avolio et al.",

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T1 - Cardiac pericyte reprogramming by MEK inhibition promotes arteriologenesis and angiogenesis of the ischemic heart

AU - Avolio, Elisa

AU - Katare, Rajesh G

AU - Thomas, Anita C

AU - Caporali, Andrea

AU - Schwenke, Daryl

AU - Carrabba, Michele

AU - Meloni, Marco

AU - Caputo, Massimo

AU - Madeddu, Paolo R

N1 - Funding Information: We wish to acknowledge the Wolfson Bioimaging Facility, University of Bristol, for the access to confocal microscopes and expert technical advice. We also acknowledge the University of Edinburgh Bioresearch & Veterinary Services at the Little France Facility for supporting the in vivo Matrigel experiment. Drawings were created with BioRender.com. This work was funded by the British Heart Foundation Centre for Regenerative Medicine Award (II) - “Centre for Vascular Regeneration” (RM/17/3/33381) to PM (co-lead of Work Package 3). In addition, it was supported by a grant from the National Institute for Health Research (NIHR) Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. EA was a Research Associate supported by the British Heart Foundation. M Caputo is a British Heart Foundation Professor of Cardiac Surgery. Publisher Copyright: © 2022, Avolio et al.

PY - 2022/5/16

Y1 - 2022/5/16

N2 - Pericytes (PC) are abundant yet remain the most enigmatic and ill-defined cell population in the heart. Here, we investigated if PC can be reprogrammed to aid neovascularization. Primary PC from human and mouse hearts acquired cytoskeleton proteins typical of vascular smooth muscle cells (VSMC) upon exclusion of EGF/bFGF, which signal through ERK1/2, or exposure to the MEK-inhibitor PD0325901. Differentiated PC became more proangiogenic, more responsive to vasoactive agents, and insensitive to chemoattractants. RNA-Sequencing revealed transcripts marking the PD0325901-induced transition into proangiogenic, stationary VSMC-like cells, including the unique expression of two angiogenesis-related markers, aquaporin 1 (AQP1) and cellular retinoic acid-binding protein 2 (CRABP2), which were further verified at the protein level. This enabled us to trace PC during in vivo studies. In mice, implantation of Matrigel plugs containing human PC+PD0325901 promoted the formation of α-SMApos neovessels compared with PC only. Two-week oral administration of PD0325901 to mice increased the heart arteriolar density, total vascular area, arteriole coverage by PDGFRβposAQP1posCRABP2pos PC, and myocardial perfusion. Short-duration PD0325901 treatment of mice after myocardial infarction enhanced the peri-infarct vascularization, reduced the scar, and improved systolic function. In conclusion, myocardial PC have intrinsic plasticity that can be pharmacologically modulated to promote reparative vascularization of the ischemic heart.

AB - Pericytes (PC) are abundant yet remain the most enigmatic and ill-defined cell population in the heart. Here, we investigated if PC can be reprogrammed to aid neovascularization. Primary PC from human and mouse hearts acquired cytoskeleton proteins typical of vascular smooth muscle cells (VSMC) upon exclusion of EGF/bFGF, which signal through ERK1/2, or exposure to the MEK-inhibitor PD0325901. Differentiated PC became more proangiogenic, more responsive to vasoactive agents, and insensitive to chemoattractants. RNA-Sequencing revealed transcripts marking the PD0325901-induced transition into proangiogenic, stationary VSMC-like cells, including the unique expression of two angiogenesis-related markers, aquaporin 1 (AQP1) and cellular retinoic acid-binding protein 2 (CRABP2), which were further verified at the protein level. This enabled us to trace PC during in vivo studies. In mice, implantation of Matrigel plugs containing human PC+PD0325901 promoted the formation of α-SMApos neovessels compared with PC only. Two-week oral administration of PD0325901 to mice increased the heart arteriolar density, total vascular area, arteriole coverage by PDGFRβposAQP1posCRABP2pos PC, and myocardial perfusion. Short-duration PD0325901 treatment of mice after myocardial infarction enhanced the peri-infarct vascularization, reduced the scar, and improved systolic function. In conclusion, myocardial PC have intrinsic plasticity that can be pharmacologically modulated to promote reparative vascularization of the ischemic heart.

KW - pericytes

KW - arteriologenesis

KW - MEK inhibitor

KW - myocardial ischemia

KW - angiogenesis

U2 - 10.1172/JCI152308

DO - 10.1172/JCI152308

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JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 10

M1 - e152308

ER -

Cardiac pericyte reprogramming by MEK inhibition promotes arteriologenesis and angiogenesis of the ischemic heart

Abstract

Bibliographical note

Research Groups and Themes

Keywords

Access to Document

Handle.net

Embargoed Document

Fingerprint

Research output

Transcriptomics signature of human heart vascular pericytes - Expression profiling by high throughput sequencing (Accession number GSE195917)

Cardiac pericytes can be pharmacologically redirected towards a smooth muscle phenotype to enhance the revascularisation of the ischemic heart

A short term treatment with a Mek1/2 inhibitor promotes myocardial arteriogenesis and perfusion in vivo: focus on cardiac mural cells

Prizes

BHF Reflections of Research Science Image competition

Young Investigator Award in Vascular Biology

Cite this