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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.

SUBMITTER: Quijada P

PROVIDER: S-EPMC10178847 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Cardiac pericytes mediate the remodeling response to myocardial infarction.

Quijada Pearl P Park Shuin S Zhao Peng P Kolluri Kamal Ss KS Wong David D Shih Kevin D KD Fang Kai K Pezhouman Arash A Wang Lingjun L Daraei Ali A Tran Matthew D MD Rathbun Elle M EM Burgos Villar Kimberly N KN Garcia-Hernandez Maria L ML Pham Thanh Td TT Lowenstein Charles J CJ Iruela-Arispe M Luisa ML Carmichael S Thomas ST Small Eric M EM Ardehali Reza R

The Journal of clinical investigation 20230515 10

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 permeabili ...[more]

PMID: 37183820

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Project description:AimsRetinoic acid receptor-related orphan nuclear receptor γt (RORγt) is a transcriptional factor responsible for IL-17-producing T-cell differentiation. Although it was demonstrated that RORγt plays essential roles in the onset of autoimmune myocarditis, pathophysiological significance of RORγt in cardiac remodeling after myocardial infarction (MI) remains to be fully elucidated.Methods and resultsMI was generated by ligating coronary artery. The expression of RORγt and IL-17A transcripts increased in murine hearts after MI. Additionally, immunohistochemical staining revealed that RORγt-expressing cells infiltrated in the border zone after MI. Flow cytometric analysis showed that RORγt-expressing cells were released from the spleen at day 1 after MI. Though RORγt-expressing cells in spleen expressed γδTCR or CD4, γδTCR+ cells were major population of RORγt-expressing cells that infiltrated into post-infarct myocardium. To address the biological functions of RORγt-expressing cells in infarcted hearts, we used mice with enhanced GFP gene heterozygously knocked-in at RORγt locus (RORγt+/- mice), which physiologically showed reduced expression of RORγt mRNA in thymus. Kaplan-Meier analysis showed that MI-induced mortality was higher in RORγt+/- mice than wild-type (WT) mice. Masson's trichrome staining demonstrated that cardiac injury was exacerbated in RORγt+/- mice 7 days after MI (Injured area: RORγt+/-; 42.1±6.5%, WT; 34.0±3.7%, circumference of injured myocardium: RORγt+/-; 61.8±4.8%, WT; 49.6±5.1%), accompanied by exacerbation of cardiac function (fractional shortening: RORγt+/-; 32.9±2.9%, WT; 38.3±3.6%). Moreover, immunohistochemical analyses revealed that capillary density in border zone was significantly reduced in RORγt+/- mice after MI, compared with WT mice, associated with the reduced expression of angiopoietin 2. Finally, the mRNA expression of RORγt, IL-17A, IL-17F and IL-23 receptor (IL-23R) mRNA and protein expression of IL-10 were decreased in RORγt+/- hearts.ConclusionsHeterozygous deletion of RORγt gene resulted in aggravated cardiac remodeling, accompanied by reduced capillary density, after MI, suggesting that RORγt-expressing cells contribute to tissue repair in infarcted myocardium.

Project description:BackgroundPericytes have been implicated in tissue repair, remodeling, and fibrosis. Although the mammalian heart contains abundant pericytes, their fate and involvement in myocardial disease remains unknown.MethodsWe used NG2Dsred;PDGFRαEGFP pericyte:fibroblast dual reporter mice and inducible NG2CreER mice to study the fate and phenotypic modulation of pericytes in myocardial infarction. The transcriptomic profile of pericyte-derived cells was studied using polymerase chain reaction arrays and single-cell RNA sequencing. The role of transforming growth factor-β (TGF-β) signaling in regulation of pericyte phenotype was investigated in vivo using pericyte-specific TGF-β receptor 2 knockout mice and in vitro using cultured human placental pericytes.ResultsIn normal hearts, neuron/glial antigen 2 (NG2) and platelet-derived growth factor receptor α (PDGFRα) identified distinct nonoverlapping populations of pericytes and fibroblasts, respectively. After infarction, a population of cells expressing both pericyte and fibroblast markers emerged. Lineage tracing demonstrated that in the infarcted region, a subpopulation of pericytes exhibited transient expression of fibroblast markers. Pericyte-derived cells accounted for ~4% of PDGFRα+ infarct fibroblasts during the proliferative phase of repair. Pericyte-derived fibroblasts were overactive, expressing higher levels of extracellular matrix genes, integrins, matricellular proteins, and growth factors, when compared with fibroblasts from other cellular sources. Another subset of pericytes contributed to infarct angiogenesis by forming a mural cell coat, stabilizing infarct neovessels. Single-cell RNA sequencing showed that NG2 lineage cells diversify after infarction and exhibit increased expression of matrix genes, and a cluster with high expression of fibroblast identity markers emerges. Trajectory analysis suggested that diversification of infarct pericytes may be driven by proliferating cells. In vitro and in vivo studies identified TGF-β as a potentially causative mediator in fibrogenic activation of infarct pericytes. However, pericyte-specific TGF-β receptor 2 disruption had no significant effects on infarct myofibroblast infiltration and collagen deposition. Pericyte-specific TGF-β signaling was involved in vascular maturation, mediating formation of a mural cell coat investing infarct neovessels and protecting from dilative remodeling.ConclusionsIn the healing infarct, cardiac pericytes upregulate expression of fibrosis-associated genes, exhibiting matrix-synthetic and matrix-remodeling profiles. A fraction of infarct pericytes exhibits expression of fibroblast identity markers. Pericyte-specific TGF-β signaling plays a central role in maturation of the infarct vasculature and protects from adverse dilative remodeling, but it does not modulate fibrotic remodeling.

Project description:Pericytes have been implicated in regulation of inflammatory, reparative, fibrogenic and angiogenic responses in several different organs and pathologic conditions. Although the adult mammalian heart contains abundant pericytes, their fate and involvement in myocardial disease remains unknown. We used NG2Dsred;PDGFRaEGFP pericyte-fibroblast dual reporter mice and inducible NG2CreER mice to study the fate and phenotypic modulation of pericytes in a model of myocardial infarction. The transcriptomic profile of pericyte-derived fibroblasts was studied using PCR arrays. The transcriptomic profile of NG2 lineage cells (pericytes) was studied in control and infarcted hearts using single cell RNA-sequencing analysis. The role of TGF-b signaling in regulation of pericyte phenotype in vivo was investigated using pericyte-specific Tgfbr2 knockout mice. In vitro, the effects of TGF-b were studied in cultured human placental pericytes.In normal mouse hearts, NG2 and PDGFRa identified distinct non-overlapping populations of pericytes and fibroblasts respectively. Following myocardial infarction, a population of cells expressing both pericyte and fibroblast markers emerged. These cells expressed large amounts of extracellular matrix (ECM) genes. Lineage tracing demonstrated that in the infarcted region, a subpopulation of pericytes underwent fibroblast conversion. Single cell RNA-seq experiments demonstrated expansion and diversification of pericyte-derived cells in the infarct, associated with emergence of subpopulations exhibiting accentuated matrix gene synthesis. In vitro studies and the profile of pericyte-derived fibroblasts identified TGF-b as a potentially causative mediator in fibrogenic activation of infarct pericytes. However, pericyte-specific Tgfbr2 disruption had no significant effects on myofibroblast infiltration and collagen deposition in the infarct. Pericyte-specific TGF-b signaling was involved in vascular maturation, mediating formation of a mural cell coat investing infarct neovessels. These reparative effects of infarct pericytes protected the infarcted heart from dilative remodeling.

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Cardiac pericytes mediate the remodeling response to myocardial infarction.

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Cardiac pericytes mediate the remodeling response to myocardial infarction.

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