The Role of Platelet-Derived Growth Factor Signaling in Healing Myocardial Infarcts

Pawel Zymek, Marcin Bujak, Khaled Chatila, Anna Cieslak, Geeta Thakker, Mark L. Entman, Nikolaos G. Frangogiannis

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2315-2323
Number of pages9
JournalJournal of the American College of Cardiology
Volume48
Issue number11
DOIs
StatePublished - Dec 5 2006
Externally publishedYes

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Platelet-Derived Growth Factor Receptors
Platelet-Derived Growth Factor
Myocardial Infarction
Proto-Oncogene Proteins c-sis
Blood Vessels
Collagen
Reperfusion
Antibodies

ASJC Scopus subject areas

  • Nursing(all)

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The Role of Platelet-Derived Growth Factor Signaling in Healing Myocardial Infarcts. / Zymek, Pawel; Bujak, Marcin; Chatila, Khaled; Cieslak, Anna; Thakker, Geeta; Entman, Mark L.; Frangogiannis, Nikolaos G.

In: Journal of the American College of Cardiology, Vol. 48, No. 11, 05.12.2006, p. 2315-2323.

Research output: Contribution to journalArticle

Zymek, Pawel ; Bujak, Marcin ; Chatila, Khaled ; Cieslak, Anna ; Thakker, Geeta ; Entman, Mark L. ; Frangogiannis, Nikolaos G. / The Role of Platelet-Derived Growth Factor Signaling in Healing Myocardial Infarcts. In: Journal of the American College of Cardiology. 2006 ; Vol. 48, No. 11. pp. 2315-2323.
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AU - Bujak, Marcin

AU - Chatila, Khaled

AU - Cieslak, Anna

AU - Thakker, Geeta

AU - Entman, Mark L.

AU - Frangogiannis, Nikolaos G.

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