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 Article has an altmetric score of 71

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 4

Signaling studies in cardiac PCs.

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Signaling studies in cardiac PCs. (A–C) Phospho-kinase array. For a quic...
(A–C) Phospho-kinase array. For a quick screening of the intracellular signaling activated by EGF and bFGF in cardiac PCs, we performed a human phospho-kinase protein array (n = 2 patients’ PCs). The array allowed the detection of the phosphorylation of 43 kinases. (A) Experimental protocol. (B) Membranes representative of n = 1 PC. (C) Targets whose phosphorylation was induced by EGF and bFGF. Densitometry graphs show the quantification of all replicate spots from n = 2 patients’ PCs (2 spots each). Data are presented as individual values and mean ± SEM. No statistical tests were applied. (D) Western blot indicating the activation of EGFR/FGFR/ERK1/-2/ELK1 signaling by EGF and bFGF in cardiac PCs. n = 3 patients’ PCs, indicated by A, B, and C.