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ProNGF, a cytokine induced after myocardial infarction in humans, targets pericytes to promote microvascular damage and activation.

ABSTRACT: Treatment of acute cardiac ischemia focuses on reestablishment of blood flow in coronary arteries. However, impaired microvascular perfusion damages peri-infarct tissue, despite arterial patency. Identification of cytokines that induce microvascular dysfunction would provide new targets to limit microvascular damage. Pro-nerve growth factor (NGF), the precursor of NGF, is a well characterized cytokine in the brain induced by injury. ProNGF activates p75 neurotrophin receptor (p75(NTR)) and sortilin receptors to mediate proapoptotic responses. We describe induction of proNGF by cardiomyocytes, and p75(NTR) in human arterioles after fatal myocardial infarction, but not with unrelated pathologies. After mouse cardiac ischemia-reperfusion (I-R) injury, rapid up-regulation of proNGF by cardiomyocytes and p75(NTR) by microvascular pericytes is observed. To identify proNGF actions, we generated a mouse expressing a mutant Ngf allele with impaired processing of proNGF to mature NGF. The proNGF-expressing mouse exhibits cardiac microvascular endothelial activation, a decrease in pericyte process length, and increased vascular permeability, leading to lethal cardiomyopathy in adulthood. Deletion of p75(NTR) in proNGF-expressing mice rescues the phenotype, confirming the importance of p75(NTR)-expressing pericytes in the development of microvascular injury. Furthermore, deficiency in p75(NTR) limits infarct size after I-R. These studies identify novel, nonneuronal actions for proNGF and suggest that proNGF represents a new target to limit microvascular dysfunction.

SUBMITTER: Siao CJ

PROVIDER: S-EPMC3501352 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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ProNGF, a cytokine induced after myocardial infarction in humans, targets pericytes to promote microvascular damage and activation.

Siao Chia-Jen CJ Lorentz Christina U CU Kermani Pouneh P Marinic Tina T Carter John J McGrath Kelly K Padow Victoria A VA Mark Willie W Falcone Domenick J DJ Cohen-Gould Leona L Parrish Diana C DC Habecker Beth A BA Nykjaer Anders A Ellenson Lora H LH Tessarollo Lino L Hempstead Barbara L BL

The Journal of experimental medicine 20121022 12

Treatment of acute cardiac ischemia focuses on reestablishment of blood flow in coronary arteries. However, impaired microvascular perfusion damages peri-infarct tissue, despite arterial patency. Identification of cytokines that induce microvascular dysfunction would provide new targets to limit microvascular damage. Pro-nerve growth factor (NGF), the precursor of NGF, is a well characterized cytokine in the brain induced by injury. ProNGF activates p75 neurotrophin receptor (p75(NTR)) and sorti ...[more]

PMID: 23091165

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Project description:ObjectivesCardiovascular magnetic resonance-feature tracking (CMR-FT) enables quantification of myocardial deformation and may be used as an objective measure of myocardial involvement in ST-elevation myocardial infarction (STEMI). We sought to investigate the associations between myocardial dyssynchrony parameters and myocardium damage for STEMI.MethodsWe analyzed 65 patients (45-80 years old) with anterior STEMI after primary percutaneous coronary intervention during 3-7 days [observational (STEMI) group] and 60 healthy volunteers [normal control (NC) group]. Myocardial dyssynchrony parameters were derived, including global and regional strain, radial rebound stretch and displacement, systolic septal time delay, and circumferential stretch.ResultsCMR characteristics, including morphologic parameters such as left ventricular ejection fraction (LVEF) (45.3% ± 8.2%) and myocardium damage in late gadolinium enhancement (LGE) (19.4% ± 4.7% LV), were assessed in the observation group. The global radial strain (GRS) and global longitudinal strain (GLS) substantially decreased in anterior STEMI compared with the NC group (GRS: 19.4% ± 5.1% vs. 24.8% ± 4.0%, P < 0.05; GLS: -10.1% ± 1.7% vs. -13.7% ± 1.0%, P < 0.05). Among 362 infarcted segments, radial and circumferential peak strains of the infarcted zone were the lowest (14.4% ± 3.2% and -10.7% ± 1.6%, respectively). The radial peak displacement of the infarct zone significantly decreased (2.6 ± 0.4 mm) (P < 0.001) and manifested in the circumferential displacement (3.5° ± 0.7°) in the STEMI group (P < 0.01). As microvascular occlusion (MVO) was additionally present, some strain parameters were significantly impaired in LGE+/MVO+ segments (radial strain [RS]: 12.2% ± 2.1%, circumferential strain [CS]: -9.6% ± 0.7%, longitudinal strain [LS]: -6.8% ± 1.0%) compared to LGE+/MVO- (RS: 14.6% ± 3.2%, CS: -10.8% ± 1.8%, LS: -9.2% ± 1.3%) (P < 0.05). When the extent of transmural myocardial infarction is greater than 75%, the parameter of the systolic septal delay (mean, 148 ms) was significantly reduced compared to fewer degrees of infarction (P < 0.01).ConclusionIn anterior STEMI, the infarcted septum swings in a bimodal mode, and myocardial injury reduces the radial strain contractility. A more than 75% transmural degree was the septal strain-contraction reserve cut-off point.

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:Background Impaired microcirculatory reperfusion worsens prognosis following acute ST-segment-elevation myocardial infarction. In the T-TIME (A Trial of Low-Dose Adjunctive Alteplase During Primary PCI) trial, microvascular obstruction on cardiovascular magnetic resonance imaging did not differ with adjunctive, low-dose, intracoronary alteplase (10 or 20 mg) versus placebo during primary percutaneous coronary intervention. We evaluated the effects of intracoronary alteplase, during primary percutaneous coronary intervention, on the index of microcirculatory resistance, coronary flow reserve, and resistive reserve ratio. Methods and Results A prespecified physiology substudy of the T-TIME trial. From 2016 to 2017, patients with ST-segment-elevation myocardial infarction ≤6 hours from symptom onset were randomized in a double-blind study to receive alteplase 20 mg, alteplase 10 mg, or placebo infused into the culprit artery postreperfusion, but prestenting. Index of microcirculatory resistance, coronary flow reserve, and resistive reserve ratio were measured after percutaneous coronary intervention. Cardiovascular magnetic resonance was performed at 2 to 7 days and 3 months. Analyses in relation to ischemic time (<2, 2-4, and ≥4 hours) were prespecified. One hundred forty-four patients (mean age, 59±11 years; 80% male) were prospectively enrolled, representing 33% of the overall population (n=440). Overall, index of microcirculatory resistance (median, 29.5; interquartile range, 17.0-55.0), coronary flow reserve(1.4 [1.1-2.0]), and resistive reserve ratio (1.7 [1.3-2.3]) at the end of percutaneous coronary intervention did not differ between treatment groups. Interactions were observed between ischemic time and alteplase for coronary flow reserve (P=0.013), resistive reserve ratio (P=0.026), and microvascular obstruction (P=0.022), but not index of microcirculatory resistance. Conclusions In ST-segment-elevation myocardial infarction with ischemic time ≤6 hours, there was overall no difference in microvascular function with alteplase versus placebo. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT02257294.

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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ProNGF, a cytokine induced after myocardial infarction in humans, targets pericytes to promote microvascular damage and activation.

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ProNGF, a cytokine induced after myocardial infarction in humans, targets pericytes to promote microvascular damage and activation.

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