The role of platelet-derived growth factor signaling in healing myocardial infarcts.
OBJECTIVE
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
Pawel
P
Section of Cardiovascular Sciences, the DeBakey Heart Center, Baylor College of Medicine, and the Methodist Hospital, Houston, Texas 77030, USA.
Bujak
Marcin
M
Chatila
Khaled
K
Cieslak
Anna
A
Thakker
Geeta
G
Entman
Mark L
ML
Frangogiannis
Nikolaos G
NG
D000818:Animals; D001808:Blood Vessels / Q000473:pathology; D002921:Cicatrix / Q000503:physiopathology; D003094:Collagen / Q000378:metabolism; D005355:Fibrosis; D007249:Inflammation / Q000503:physiopathology; D007962:Leukocytes / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism*; D015398:Signal Transduction; D014018:Tissue Distribution; D014945:Wound Healing
D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; C075278:platelet-derived growth factor A; D003094:Collagen; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor