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 4

Cspg4-lineage cardiac pericytes proliferate in the infarcted area.

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Cspg4-lineage cardiac pericytes proliferate in the infarcted area. (A) ...
(A) Schematic of BrdU administration. After surgery, Cspg4CreER/+ Rosa26tdT/+ mice received a single injection of BrdU, followed by ad libitum administration of water containing BrdU. (B) Flow cytometric analysis of the percentage of BrdU+tdTomato+ cells in Cspg4CreER/+ Rosa26tdT/+ mouse hearts that had undergone sham or MI operation. n = 4 sham, 2dMI, 4dMI, 7dMI hearts and n = 3 14dMI hearts. Data were analyzed by 1-way ANOVA with Tukey’s multiple-comparison test. (C) Schematic of Cspg4CreER/+ Rosa26tdT/+ mice subjected to single injections of EdU for 4 hours at specified MI time points. Analyses are representative of four 2dMI, 4dMI, and 7dMI experiments, and three 14dMI experiments. (D) Proliferating (EdU+, white) tdTomato+ cells were found within the BZ and infarct area (arrows) but not in the remote area. Scale bars: 50 μm. (E) Representative images show the localization of tdTomato+ cells in the remote and infarct areas during MI. Scale bars: 50 μm (remote and infarct regions) and 1 mm (whole heart images). Images are representative of four 2dMI, 4dMI, 14dMI experiments, and three 7dMI experiments. The (F) percentage and (G) number of tdTomato+ cells in the fibrotic regions of the heart increased during MI and relative to the remote region. n = 3 sham, 2dMI, 4dMI, and 14dMI hearts and n = four 7dMI hearts. Data were analyzed by 1-way ANOVA with Tukey’s multiple-comparison test. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.