In mice with reperfused myocardial infarction, PDGFR-beta blockade impaired vascular maturation and decreased collagen, while PDGFR-alpha inhibition decreased collagen without affecting maturation.
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.
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.
Zymek et al. (Tue,) conducted a other in 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.