Cardiac pericyte reprogramming by MEK inhibition promotes arteriologenesis and angiogenesis of the ischemic heart
Elisa Avolio, … , Massimo Caputo, Paolo Madeddu
Elisa Avolio, … , Massimo Caputo, Paolo Madeddu
Published March 29, 2022
Citation Information: J Clin Invest. 2022;132(10):e152308. https://doi.org/10.1172/JCI152308.
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Research Article Angiogenesis Vascular biology

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

Abstract

Pericytes (PCs) are abundant yet remain the most enigmatic and ill-defined cell population in the heart. Here, we investigated whether PCs can be reprogrammed to aid neovascularization. Primary PCs from human and mouse hearts acquired cytoskeletal proteins typical of vascular smooth muscle cells (VSMCs) upon exclusion of EGF/bFGF, which signal through ERK1/2, or upon exposure to the MEK inhibitor PD0325901. Differentiated PCs 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 2 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 PCs during in vivo studies. In mice, implantation of Matrigel plugs containing human PCs plus PD0325901 promoted the formation of αSMA+ neovessels compared with PC only. Two-week oral administration of PD0325901 to mice increased the heart arteriolar density, total vascular area, arteriole coverage by PDGFRβ+AQP1+CRABP2+ PCs, 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 PCs have intrinsic plasticity that can be pharmacologically modulated to promote reparative vascularization of the ischemic heart.

Authors

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

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Figure 1

Human cardiac PC antigenic and functional characterization.

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Human cardiac PC antigenic and functional characterization. (A–C) Confoc...
(A–C) Confocal immunofluorescence images of human hearts. Arrows point to CD31–CD34+PDGFRβ+αSMA– PCs around capillaries (indicated with “C”) and arterioles. Scale bars: 20 μm (A and B) and 100 μm (C). (D) Immunofluorescence images and bar graphs showing PC antigenic profile at passage 5 of culture. Scale bars: 50 μm. n = 3 patients’ PCs. Representative images are from 1 patient. (E and F) Expression of TCF21 in cardiac PCs and fibroblasts evaluated by RT-qPCR (E) and Western blotting (F). n = 4 fibroblasts in E (from 2 donors, assayed in independent experimental duplicates) and n = 3 fibroblast donors in F, n = 5 patients’ PCs. (G) Angiogenic factors secreted by cardiac PCs. Amounts of secreted factors throughout 48 hours were normalized against the total intracellular protein content. n = 6 patients’ PCs. (H) 2D-Matrigel assay with human coronary artery ECs (CAECs) in monoculture or coculture with cardiac PCs. PCs were labeled with dil (red fluorescent dye). Black arrowheads point to examples of PCs. n = 5 patients’ PCs, n = 1 CAEC. Representative images are from 1 patient’s PCs. All data are presented as individual values and mean ± SEM. *P < 0.05; **P < 0.01 by unpaired Mann-Whitney U test.