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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, the DeBakey Heart Center, Baylor College of Medicine, and the Methodist Hospital, Houston, Texas
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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