The role of platelet-derived growth factor signaling in healing myocardial infarcts
| Autor: | Pawel Zymek, Anna Cieslak, Mark L. Entman, Geeta D. Thakker, Marcin Bujak, Khaled Chatila, Nikolaos G. Frangogiannis |
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| Rok vydání: | 2006 |
| Předmět: |
Platelet-derived growth factor
Receptor Platelet-Derived Growth Factor alpha medicine.medical_treatment Myocardial Infarction 030204 cardiovascular system & hematology chemistry.chemical_compound Mice 0302 clinical medicine Fibrosis Leukocytes Receptors Platelet-Derived Growth Factor Tissue Distribution Phosphorylation Platelet-Derived Growth Factor 0303 health sciences biology Proto-Oncogene Proteins c-sis Extravasation medicine.anatomical_structure embryonic structures cardiovascular system Collagen medicine.symptom Cardiology and Cardiovascular Medicine tissues Platelet-derived growth factor receptor Signal Transduction medicine.medical_specialty Neovascularization Physiologic Inflammation Mural cell Receptor Platelet-Derived Growth Factor beta 03 medical and health sciences Cicatrix Internal medicine medicine Animals 030304 developmental biology Wound Healing business.industry Growth factor Monocyte Microcirculation Myocardium medicine.disease Mice Inbred C57BL enzymes and coenzymes (carbohydrates) Endocrinology chemistry biology.protein Blood Vessels business |
| Zdroj: | Journal of the American College of Cardiology. 48(11) |
| ISSN: | 1558-3597 |
| Popis: | Objectives This study sought to examine the role of platelet-derived growth factor (PDGF) signaling in healing myocardial infarcts. Background Platelet-derived growth factor isoforms exert potent fibrogenic effects through interactions with PDGF receptor (PDGFR)-α and PDGFR-β. In addition, PDGFR-β signaling mediates coating of developing vessels with mural cells, leading to the formation of a mature vasculature. We hypothesized that PDGFR activation may regulate fibrosis and vascular maturation in healing myocardial infarcts. Methods Mice undergoing reperfused infarction protocols were injected daily with a neutralizing anti–PDGFR-β antibody (APB5), an anti-PDGFR-α antibody (APA5), or control immunoglobulin G, and were killed after 7 days of reperfusion. Results The PDGF-B, PDGFR-α, and PDGFR-β mRNA expression was induced in reperfused mouse infarcts. Perivascular cells expressing phosphorylated PDGFR-β were identified in the infarct after 7 days of reperfusion, indicating activation of the PDGF-BB/PDGFR-β pathway. The PDGFR-β blockade resulted in impaired maturation of the infarct vasculature, enhanced capillary density, and formation of dilated uncoated vessels. Defective vascular maturation in antibody-treated mice was associated with increased and prolonged extravasation of red blood cells and monocyte/macrophages, suggesting increased permeability. These defects resulted in decreased collagen content in the healing infarct. In contrast, PDGFR-α inhibition did not affect vascular maturation, but significantly decreased collagen deposition in the infarct. Conclusions Platelet-derived growth factor signaling critically regulates postinfarction repair. Both PDGFR-β– and PDGFR-α–mediated pathways promote collagen deposition in the infarct. Activation of PDGF-B/PDGFR-β is also involved in recruitment of mural cells by neovessels, regulating maturation of the infarct vasculature. Acquisition of a mural coat and maturation of the vasculature promotes resolution of inflammation and stabilization of the scar. |
| Databáze: | OpenAIRE |
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