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PRECLINICAL STUDY

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

Pawel Zymek, MD^_*, Marcin Bujak, MD^_*, Khaled Chatila, MD^_*, Anna Cieslak, MS^_*, Geeta Thakker, PhD, Mark L. Entman, MD, FACC^_* and Nikolaos G. Frangogiannis, MD, FACC^_*,_*

^_* Section of Cardiovascular Sciences
Section of Atherosclerosis, the DeBakey Heart Center, Baylor College of Medicine, and the Methodist Hospital, Houston, Texas

Manuscript received June 1, 2006; revised manuscript received July 13, 2006, accepted July 17, 2006.

^_* Reprint requests and correspondence: Dr. Nikolaos G. Frangogiannis, Section of Cardiovascular Sciences, One Baylor Plaza, M/S F-602, Baylor College of Medicine, Houston, Texas 77030 (Email: ngf{at}bcm.tmc.edu).

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)- and PDGFR-ß. In addition, PDGFR-ß 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-ß antibody (APB5), an anti-PDGFR- antibody (APA5), or control immunoglobulin G, and were killed after 7 days of reperfusion.

RESULTS: The PDGF-B, PDGFR-, and PDGFR-ß mRNA expression was induced in reperfused mouse infarcts. Perivascular cells expressing phosphorylated PDGFR-ß were identified in the infarct after 7 days of reperfusion, indicating activation of the PDGF-BB/PDGFR-ß pathway. The PDGFR-ß 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- 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-ß– and PDGFR-–mediated pathways promote collagen deposition in the infarct. Activation of PDGF-B/PDGFR-ß 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.

Abbreviations and Acronyms   APA = anti–PDGFR- antibody   APB = anti–PDGFR-ß antibody   IgG = immunoglobulin G   PCR = polymerase chain reaction   PDGF = platelet-derived growth factor   PDGFR = platelet-derived growth factor receptor   SMA = smooth muscle actin

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