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

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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 languageEnglish
Article numbere152308
Pages (from-to)1-17
JournalJournal of Clinical Investigation
Issue number10
Early online date26 Mar 2022
Publication statusPublished - 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 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.

Structured keywords

  • Bristol Heart Institute


  • pericytes
  • arteriologenesis
  • MEK inhibitor
  • myocardial ischemia
  • angiogenesis


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