Placenta growth factor in diabetic wound healing: altered expression and therapeutic potential.
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.
Cianfarani
Francesca
F
Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Via dei Monti di Creta, 104, 00167 Rome, Italy.
Zambruno
Giovanna
G
Brogelli
Laura
L
Sera
Francesco
F
Lacal
Pedro Miguel
PM
Pesce
Maurizio
M
Capogrossi
Maurizio C
MC
Failla
Cristina Maria
CM
Napolitano
Monica
M
Odorisio
Teresa
T
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002465:Cell Movement; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000235:genetics* / Q000378:metabolism*; D012867:Skin / Q000166:cytology / Q000293:injuries*; D015533:Transcriptional Activation; D014945:Wound Healing / Q000235:genetics
C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor