TY - JOUR
T1 - The Role of Platelet-Derived Growth Factor Signaling in Healing Myocardial Infarcts
AU - Zymek, Pawel
AU - Bujak, Marcin
AU - Chatila, Khaled
AU - Cieslak, Anna
AU - Thakker, Geeta
AU - Entman, Mark L.
AU - Frangogiannis, Nikolaos G.
PY - 2006/12/5
Y1 - 2006/12/5
N2 - 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.
AB - 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.
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U2 - 10.1016/j.jacc.2006.07.060
DO - 10.1016/j.jacc.2006.07.060
M3 - Article
C2 - 17161265
AN - SCOPUS:33845220020
SN - 0735-1097
VL - 48
SP - 2315
EP - 2323
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 11
ER -