Recombinant AAV vector encoding human VEGF165 enhances wound healing

Deodato, Barbara; Arsic, Nikola; Zentilin, Lorena; Galeano, Mariarosaria; Santoro, Daniela; Torre, Valerio; Altavilla, Domenica; Valdembri, Donatella; Bussolino, Federico; Squadrito, Francesco; Giacca, Mauro

doi:10.1038/sj.gt.3301697

Cited by 121 publications

(70 citation statements)

References 48 publications

(43 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The wound healing process of normoglycaemic animals was also improved by the gene transfer of human VEGF, as shown previously [46]. Furthermore PBS-treated wounds healed similarly to wounds treated with the control and inert gene rAAV-LacZ.…”

Section: Discussionsupporting

confidence: 80%

“…Indeed rAAV vectors seem to have a particular tropism for the skin: as a matter of fact transgene expression in the interfollicular epidermis and in the panniuclus carnosus, a layer of skeletal muscle underlying the dermis, is remarkable within 7 to 10 days [46]. In contrast experimental evidences suggest that the transgene expression of rAAV vectors in other tissues (such as the heart, brain and the liver) requires at least 3 to 4 weeks [26,27,28].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Adeno-associated viral vector-mediated human vascular endothelial growth factor gene transfer stimulates angiogenesis and wound healing in the genetically diabetic mouse

et al. 2003

View full text Add to dashboard Cite

Aims/hypothesis. We studied the gene therapy efficacy of diabetes-associated wound healing disorder with an adeno-associated virus (AAV) vector expressing the 165-amino acid isoform of human vascular endothelial growth factor-A (VEGF-A) by using an incisional skin-wound model produced on the back of female diabetic C57BL/KsJ db+/db+ mice and their normal littermates (db+/+m). Methods. Animals were randomized to receive intradermally into the wound edges either rAAV-LacZ (a control gene), or rAAV-VEGF165. Animals were killed on different days (7 and 14 days after skin injury) and wounded skin tissues were used for gene marker studies, histological evaluation and immunohistochemistry, and wound breaking strength analysis. Furthermore we studied the VEGF mature protein in the wounds. Results. We found that AAV vectors are highly efficient for gene transfer to the mouse skin, displaying an exquisite tropism for the panniculus carnosus by using the beta-galactosidase activity assay. We confirmed the increased expression of the angiogenic factor at day 7 by measuring the wound content of the mature protein. Delivery of VEGF165 to incisional skin wounds of diabetic mice resulted in a remarkable induction of new vessel formation with consequent improvement in the wound healing process. The rAAV-VEGF165 gene improved wound healing in diabetic mice through the stimulation of angiogenesis, reepithelization, synthesis and maturation of extracellular matrix. Moreover the recombinant AAV encoding the human VEGF165 increased the breaking strenght of the wound and enhanced the wound content of VEGF. Conclusion/interpretation. Our study suggests that VEGF gene transfer might represent a new approach to treat wound healing disorders associated with diabetes. [Diabetologia (2003) 46:546-555]

show abstract

Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Adeno-associated viral vector-mediated human vascular endothelial growth factor gene transfer stimulates angiogenesis and wound healing in the genetically diabetic mouse

et al. 2003

View full text Add to dashboard Cite

show abstract

“…Furthermore, it should be noted that adenoviral overexpression of VEGF isoforms (VEGF121 and VEGF165) or topical treatment with VEGF does accelerate wound healing, enhances wound vascularity and increases bursting strength of wounds in mice and rats. [31][32][33][34][35] The overall small impact of antiangiogenic therapy on wound healing may result from the fact that wound healing is a complex coordinated process encompassing a variety of different cell types (keratinocytes, endothelial cells, fibroblasts, inflammatory cells, epidermal cells) and growth factors other than VEGF such as basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), keratinocyte growth factor (KGF). Thus, despite an impairment of wound angiogenesis, redundant mechanisms not further analyzed in this study appear to prevent a gross delay in wound closure.…”

Section: Discussionmentioning

confidence: 99%

Discordant effects of a soluble VEGF receptor on wound healing and angiogenesis

et al. 2004

View full text Add to dashboard Cite

Soluble receptors to vascular endothelial growth factor (VEGF) can inhibit its angiogenic effect. Since angiogenesis is involved in wound repair, we hypothesized that adenovirus-mediated gene transfer of a soluble form of VEGF receptor 2 (Flk-1) would attenuate wound healing in mice. C57Bl/6J and genetically diabetic (db/db) mice (each n¼20) received intravenous (i.v.) injections of recombinant adenoviruses (10 9 PFU) encoding the ligand-binding ectodomain of VEGF receptor 2 (Flk-1) or cDNA encoding the murine IgG2a Fc fragment (each n¼10). At 4 days after gene transfer, two full-thickness skin wounds (0.8 cm) were created on the dorsum of each animal. Wound closure was measured over 9-14 days after which wounds were resected for histological analysis. Prior to killing, fluorescent microspheres were systemically injected for quantitation of wound vascularity. Single i.v. injections of adenoviruses encoding soluble Flk-1 significantly decreased wound angiogenesis in both wild-type and diabetic mice. Fluorescence microscopy revealed a 2.0-fold (wild type) and 2.9-fold (diabetic) reduction in wound vascularity in Flk-1-treated animals (po0.05). Impairment of angiogenesis was confirmed by CD31 immunohistochemistry. Interestingly, despite significant reductions in wound vascularity, wound closure was not grossly delayed. Our data indicates that while VEGF function is essential for optimal wound angiogenesis, it is not required for wound closure.

show abstract

“…[27][28][29] Data on neovascularization of biomaterials are based today mainly on semiquantitative histological studies. 10,19,29,30 The dynamic temporal course of neovascularization was previously evaluated by means of magnetic resonance imaging techniques in animals 31 as well as in humans. 32 Using a corneal micropocket model, angiogenesis into biodegradable hydrogel implant could be assessed over long time by means of biomicroscopy.…”

Section: Discussionmentioning

confidence: 99%

“…Polymer composition can be modified by varying the weight percentages of PEGT and PBT or by changing the molecular weight (MW) of the PEG. The scaffolds used in the current study were produced by solvent-casting, particulate-leaching 19 using a copolymer with a composition PEGT/PBT weight ratio of 55/45 and PEG MW of 300 (300PEGT55/ PBT45). This composition supported the growth of fibroblasts and keratinocytes.…”

Section: Surgical Proceduresmentioning

confidence: 99%

Neovascularization of poly(ether ester) block‐copolymer scaffolds in vivo: Long‐term investigations using intravital fluorescent microscopy

Druecke

Langer

Lamme³

et al. 2003

J Biomedical Materials Res

167

137

View full text Add to dashboard Cite

Poly(ether ester) block-copolymer scaffolds of different pore size were implanted into the dorsal skinfold chamber of balb/c mice. Using intravital fluorescent microscopy, the temporal course of neovascularization into these scaffolds was quantitatively analyzed. Three scaffold groups (diameter, 5 mm; 220 -260 thickness, m; n ϭ 30) were implanted. Different pore sizes were evaluated: small (20 -75 m), medium (75-212 m) and large pores (250 -300 m). Measurements were performed on days 8, 12, 16, and 20 in the surrounding normal tissue, in the border zone, and in the center of the scaffold. Standard microcirculatory parameters were assessed (plasma leakage, vessel diameter, red blood cell velocity, and functional vessel density). The largepored scaffolds showed significantly higher functional vessel density in the border zone and in the center (days 8 and 12) compared with the scaffold with the small and mediumsized pores. These data correlated with a larger vessel diameter and a higher red blood cell velocity in the largepored scaffold group. Interestingly, during the evaluation period the microcirculatory parameters on the edge of the scaffolds returned to values similar to those found in the surrounding tissue. In the center of the scaffold, however, neovascularization was still active 20 days after implantation. Plasma leakage and vessel diameter were higher in the center of the scaffold. Red blood cell velocity and functional vessel density were 50% lower than in the surrounding tissue. In conclusion, the dorsal skinfold chamber model in mice allows long-term study of blood vessel growth and remodeling in porous biomedical materials. The rate of vessel ingrowth into poly(ether ester) block-copolymer scaffolds is influenced by pore size and was highest in the scaffold with the largest pores. The data generated with this model contribute to knowledge about the development of functional vessels and tissue ingrowth into biomaterials.

show abstract

Recombinant AAV vector encoding human VEGF165 enhances wound healing

Cited by 121 publications

References 48 publications

Adeno-associated viral vector-mediated human vascular endothelial growth factor gene transfer stimulates angiogenesis and wound healing in the genetically diabetic mouse

Adeno-associated viral vector-mediated human vascular endothelial growth factor gene transfer stimulates angiogenesis and wound healing in the genetically diabetic mouse

Discordant effects of a soluble VEGF receptor on wound healing and angiogenesis

Neovascularization of poly(ether ester) block‐copolymer scaffolds in vivo: Long‐term investigations using intravital fluorescent microscopy

Contact Info

Product

Resources

About