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(American Journal of Pathology. 2006;169:2254-2265.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060196

Platelet-Derived Growth Factor-ß Receptor Activation Is Essential for Fibroblast and Pericyte Recruitment during Cutaneous Wound Healing

Vineeth S. Rajkumar^*, Xu Shiwen^*, Maria Bostrom, Patricia Leoni^*, John Muddle, Mikael Ivarsson, Bengt Gerdin, Christopher P. Denton^*, George Bou-Gharios^¶, Carol M. Black^* and David J. Abraham^*

From the Department of Medicine,^* Centre for Rheumatology and Connective Tissue Disease, and the Department of Neurosciences, University College London, London, United Kingdom; Renal Medicine,^¶ Imperial College School of Medicine, London, United Kingdom; the Department of Surgical Sciences, Plastic Surgery Unit, Uppsala University, Uppsala, Sweden; and the Clinical Research Center, University Hospital, Örebro, Sweden

Connective tissue remodeling provides mammals with a rapid mechanism to repair wounds after injury. Inappropriate activation of this reparative process leads to scarring and fibrosis. Here, we studied the effects of platelet-derived growth factor receptor-ß blockade in vivo using the platelet-derived growth factor receptor (PDGFR)-ß inhibitor imatinib mesylate on tissue repair. After 7 days, healing of wounds was delayed with significantly reduced wound closure and concomitant reduction in myofibroblast frequency, expression of fibronectin ED-A, and collagen type I. Using a collagen type I transgenic reporter mouse, we showed that inhibiting PDGFR-ß activation restricted the distribution of collagen-synthesizing cells to wound margins and dramatically reduced cell proliferation in vivo. By 14 days, treated wounds were fully closed. Blocking PDGFR-ß signaling did not prevent the differentiation of myofibroblasts in vitro but potently inhibited fibroblast proliferation and migration. In addition, PDGFR-ß inhibition in vivo was accompanied by abnormal microvascular morphogenesis reminiscent of that observed in PDGFR-ß^–/– mice with significantly reduced immunostaining of the pericyte marker NG2. Imatinib treatment also inhibited pericyte proliferation and migration in vitro. This study highlights the significance of PDGFR-ß signaling for the recruitment, proliferation, and functional activities of fibro-blasts and pericytes during the early phases of wound healing.

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