Cardiac pericytes mediate the remodeling response to myocardial infarction
Pearl Quijada, … , Eric M. Small, Reza Ardehali
Pearl Quijada, … , Eric M. Small, Reza Ardehali
Published May 15, 2023
Citation Information: J Clin Invest. 2023;133(10):e162188. https://doi.org/10.1172/JCI162188.
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Research Article Cardiology Vascular biology

Cardiac pericytes mediate the remodeling response to myocardial infarction

Abstract

Despite the prevalence of pericytes in the microvasculature of the heart, their role during ischemia-induced remodeling remains unclear. We used multiple lineage-tracing mouse models and found that pericytes migrated to the injury site and expressed profibrotic genes, coinciding with increased vessel leakage after myocardial infarction (MI). Single-cell RNA-Seq of cardiac pericytes at various time points after MI revealed the temporally regulated induction of genes related to vascular permeability, extracellular matrix production, basement membrane degradation, and TGF-β signaling. Deleting TGF-β receptor 1 in chondroitin sulfate proteoglycan 4–expressing (Cspg4-expressing) cells reduced fibrosis following MI, leading to a transient improvement in the cardiac ejection fraction. Furthermore, genetic ablation of Cspg4-expressing cells resulted in excessive vascular permeability, a decline in cardiac function, and increased mortality in the second week after MI. These data reveal an essential role for cardiac pericytes in the control of vascular homeostasis and the fibrotic response after acute ischemic injury, information that will help guide the development of novel strategies to preserve vascular integrity and attenuate pathological cardiac remodeling.

Authors

Pearl Quijada, Shuin Park, Peng Zhao, Kamal S.S. Kolluri, David Wong, Kevin D. Shih, Kai Fang, Arash Pezhouman, Lingjun Wang, Ali Daraei, Matthew D. Tran, Elle M. Rathbun, Kimberly N. Burgos Villar, Maria L. Garcia-Hernandez, Thanh T.D. Pham, Charles J. Lowenstein, M. Luisa Iruela-Arispe, S. Thomas Carmichael, Eric M. Small, Reza Ardehali

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Figure 2

Cspg4-lineage pericytes accumulate in the infarct area and express Col1a1 after MI.

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Cspg4-lineage pericytes accumulate in the infarct area and express Col1...
(A) Breeding plan for the generation of Cspg4CreER/+ Rosa26tdT/+ Col1a1GFP/+ triple-transgenic mice. (B) Schematic for TAM injection before MI. Hearts were analyzed 2, 4, 7, and 14 days (D) after MI. (C) Representative images of the left ventricular free wall of Cspg4CreER/+ Rosa26tdT/+ Col1a1GFP/+ hearts during MI. tdTomato+GFP+ cells were observed in the infarct region (bottom) compared with the remote region (top). Scale bars: 50 μm for both infarct and remote regions. Images are representative of 4 2dMI, 4 4dMI, 3 7dMI, and 5 14dMI experiments. Arrows highlight tdTomato+GFP+ cells. (D) GFP expression in tdTomato+ (tdT+) cells increased over the MI period as analyzed by flow cytometry. n = 3 sham, n = 4 2dMI, n = 4 4dMI, n = 3 7dMI, and n = 5 14dMI hearts. (E) POSTN was expressed in tdTomato+ lineage–traced pericytes following 7 days of MI in the BZ and infarct areas but not in noninjured hearts of the sham-operated mice. Scale bars: 20 μm for infarct and remote regions. Images are representative of 3 sham and 3 7dMI experiments. (F–I) Relative gene expression of profibrotic and ECM genes in tdTomato+ cells collected via FACS from sham and MI hearts. n = 4–5 sham, n = 4–5 2dMI, n = 3 4dMI, n = 3–4 7dMI, and n = 5 14dMI hearts. *P < 0.05, **P < 0.01, and ***P < 0.001, by 1-way ANOVA with Tukey’s multiple-comparison test (D and F–I).