Placenta growth factor in diabetic wound healing - Altered expression and therapeutic potential

被引:104
作者
Cianfarani, Francesca
Zambruno, Giovanna
Brogelli, Laura
Sera, Francesco
Lacal, Pedro Miguel
Pesce, Maurizio
Capogrossi, Maurizio C.
Failla, Cristina Maria
Napolitano, Monica
Odorisio, Teresa
机构
[1] Ist Ricovero & Cura Carattere Sci, Lab Biol Mol & Cellulare, Rome, Italy
[2] Ist Ricovero & Cura Carattere Sci, Lab Patola Vascolare, Rome, Italy
[3] Ist Ricovero & Cura Carattere Sci, Mol Oncol Lab, Rome, Italy
[4] Ist Ricovero & Cura Carattere Sci, Serv Epidemiol, Rome, Italy
[5] Ist Ricovero & Cura Carattere Sci, Ist Dermopat Immacolata, Rome, Italy
[6] Ist Ricovero & Cura Carattere Sci, Lab Biol Vasc & Terapia Gen, Milan, Italy
[7] Ist Ricovero & Cura Carattere Sci, Ctr Cardiol Monzino, Milan, Italy
关键词
D O I
10.2353/ajpath.2006.051314
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
Reduced microcirculation and diminished expression of growth factors contribute to wound healing impairment in diabetes. Placenta growth factor (PIGF), 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 PIGF-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 PIGF gene transfer to diabetic wounds exerts therapeutic activity by promoting different aspects of the repair process.
引用
收藏
页码:1167 / 1182
页数:16
相关论文
共 35 条
[1]   Effect of diabetes mellitus on formation of coronary collateral vessels [J].
Abaci, A ;
Oguzhan, A ;
Kahraman, S ;
Eryol, NK ;
Ünal, S ;
Arinç, H ;
Ergin, A .
CIRCULATION, 1999, 99 (17) :2239-2242
[2]   Role of PIGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1 [J].
Autiero, M ;
Waltenberger, J ;
Communi, D ;
Kranz, A ;
Moons, L ;
Lambrechts, D ;
Kroll, J ;
Plaisance, S ;
De Mol, M ;
Bono, F ;
Kliche, S ;
Fellbrich, G ;
Ballmer-Hofer, K ;
Maglione, D ;
Mayr-Beyrle, U ;
Dewerchin, M ;
Dombrowski, S ;
Stanimirovic, D ;
Van Hummelen, P ;
Dehio, C ;
Hicklin, DJ ;
Persico, G ;
Herbert, JM ;
Communi, D ;
Shibuya, M ;
Collen, D ;
Conway, EM ;
Carmeliet, P .
NATURE MEDICINE, 2003, 9 (07) :936-943
[3]   EXPRESSION OF VASCULAR-PERMEABILITY FACTOR (VASCULAR ENDOTHELIAL GROWTH-FACTOR) BY EPIDERMAL-KERATINOCYTES DURING WOUND-HEALING [J].
BROWN, LF ;
YEO, KT ;
BERSE, B ;
YEO, TK ;
SENGER, DR ;
DVORAK, HF ;
VANDEWATER, L .
JOURNAL OF EXPERIMENTAL MEDICINE, 1992, 176 (05) :1375-1379
[4]   Placenta growth factor: Identification and characterization of a novel isoform generated by RNA alternative splicing [J].
Cao, YH ;
Ji, WDR ;
Qi, P ;
Rosin, A ;
Cao, YM .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1997, 235 (03) :493-498
[5]   VEGF gene therapy: stimulating angiogenesis or angioma-genesis? [J].
Carmeliet, P .
NATURE MEDICINE, 2000, 6 (10) :1102-1103
[6]   Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions [J].
Carmeliet, P ;
Moons, L ;
Luttun, A ;
Vincenti, V ;
Compernolle, V ;
De Mol, M ;
Wu, Y ;
Bon, F ;
Devy, L ;
Beck, H ;
Scholz, D ;
Acker, T ;
DiPalma, T ;
Dewerchin, M ;
Noel, A ;
Stalmans, I ;
Barra, A ;
Blacher, S ;
Vandendriessche, T ;
Ponten, A ;
Eriksson, U ;
Plate, KH ;
Foidart, JM ;
Schaper, W ;
Charnock-Jones, DS ;
Hicklin, DJ ;
Herbert, JM ;
Collen, D ;
Persico, MG .
NATURE MEDICINE, 2001, 7 (05) :575-583
[7]  
CIANFARANI F, GIOR ITAL DERMATOL V, V140, P497
[8]   The vascular endothelial growth factor receptor Flt-1 mediates biological activities - Implications for a functional role of placenta growth factor in monocyte activation and chemotaxis [J].
Clauss, M ;
Weich, H ;
Breier, G ;
Knies, U ;
Rockl, W ;
Waltenberger, J ;
Risau, W .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (30) :17629-17634
[9]   Recombinant AAV vector encoding human VEGF165 enhances wound healing [J].
Deodato, B ;
Arsic, N ;
Zentilin, L ;
Galeano, M ;
Santoro, D ;
Torre, V ;
Altavilla, D ;
Valdembri, D ;
Bussolino, F ;
Squadrito, F ;
Giacca, M .
GENE THERAPY, 2002, 9 (12) :777-785
[10]   Placenta growth factor is induced in human keratinocytes during wound healing [J].
Failla, CM ;
Odorisio, T ;
Cianfarani, F ;
Schietroma, C ;
Puddu, P ;
Zambruno, G .
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 2000, 115 (03) :388-395