Key result
PDGFR-beta blockade impairs vascular maturation and decreases collagen in post-MI mice, while PDGFR-alpha inhibition only reduces collagen.
Why the study?
PDGF isoforms exert potent fibrogenic and vascular maturation effects, but whether PDGFR activation regulates fibrosis and vascular maturation in healing myocardial infarcts was unclear.
Does PDGFR blockade alter fibrosis and vascular maturation in healing myocardial infarcts in mice?
Does PDGFR blockade alter fibrosis and vascular maturation in healing myocardial infarcts in mice?
Platelet-derived growth factor signaling critically regulates postinfarction repair, with both PDGFR-beta and PDGFR-alpha pathways promoting collagen deposition and PDGFR-beta regulating vascular maturation.
PDGFR inhibition should not yet alter post-MI care; leaves open isoform-specific roles in human infarct healing.
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)-alpha and PDGFR-beta. In addition, PDGFR-beta 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-beta antibody (APB5), an anti-PDGFR-alpha antibody (APA5), or control immunoglobulin G, and were killed after 7 days of reperfusion. RESULTS: The PDGF-B, PDGFR-alpha, and PDGFR-beta mRNA expression was induced in reperfused mouse infarcts. Perivascular cells expressing phosphorylated PDGFR-beta were identified in the infarct after 7 days of reperfusion, indicating activation of the PDGF-BB/PDGFR-beta pathway. The PDGFR-beta 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-alpha 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-beta- and PDGFR-alpha-mediated pathways promote collagen deposition in the infarct. Activation of PDGF-B/PDGFR-beta 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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Zymek et al. (2006) studied Myocardial Infarction. Anti-PDGFR-beta antibody (APB5) or anti-PDGFR-alpha antibody (APA5) vs. Control immunoglobulin G was evaluated on Vascular maturation and collagen deposition. In mice with reperfused myocardial infarction, PDGFR-beta blockade impaired vascular maturation and decreased collagen, while PDGFR-alpha inhibition decreased collagen without affecting maturation.
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