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(American Journal of Pathology. 2006;169:1167-1182.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.051314

Placenta Growth Factor in Diabetic Wound Healing

Altered Expression and Therapeutic Potential

Francesca Cianfarani*, Giovanna Zambruno*, Laura Brogelli*{dagger}, Francesco Sera{ddagger}, Pedro Miguel Lacal, Maurizio Pesce§, Maurizio C. Capogrossi{dagger}, Cristina Maria Failla*, Monica Napolitano{dagger} and Teresa Odorisio*

From the Laboratorio di Biologia Molecolare e Cellulare,* Laboratorio di Patologia Vascolare,{dagger} Laboratorio di Oncologia Molecolare, Servizio di Epidemiologia,{ddagger} Istituto Dermopatico dell’Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico, Rome; and Laboratorio di Biologia Vascolare e Terapia Genica,§ Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy

Reduced microcirculation and diminished expression of growth factors contribute to wound healing impairment in diabetes. Placenta growth factor (PlGF), an angiogenic mediator promoting pathophysiological neovascularization, is expressed during cutaneous wound healing and improves wound closure by enhancing angiogenesis. By using streptozotocin-induced diabetic mice, we here demonstrate that PlGF induction is strongly reduced in diabetic wounds. Diabetic transgenic mice overexpressing PlGF in the skin displayed accelerated wound closure compared with diabetic wild-type littermates. Moreover, diabetic wound treatment with an adenovirus vector expressing the human PlGF gene (AdCMV.PlGF) significantly accelerated the healing process compared with wounds treated with a control vector. The analysis of treated wounds showed that PlGF gene transfer improved granulation tissue formation, maturation, and vascularization, as well as monocytes/macrophages local recruitment. Platelet-derived growth factor, fibroblast growth factor-2, and vascular endothelial growth factor mRNA levels were increased in AdCMV.PlGF-treated wounds, possibly enhancing PlGF-mediated effects. Finally, PlGF treatment stimulated cultured dermal fibroblast migration, pointing to a direct role of PlGF in accelerating granulation tissue maturation. In conclusion, our data indicate that reduced PlGF expression contributes to impaired wound healing in diabetes and that PlGF gene transfer to diabetic wounds exerts therapeutic activity by promoting different aspects of the repair process.




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