Angiopoietin-1 gene transfer improves impaired wound healing in genetically diabetic mice without increasing VEGF expression

被引：52

作者：

Bitto, Alessandra ^{[1
]}

Minutoli, Letteria ^{[1
]}

Galeano, Maria Rosaria ^{[2
]}

Altavilla, Domenica ^{[1
]}

Polito, Francesca ^{[1
]}

Fiumara, Tiziana ^{[1
]}

Calo, Margherita ^{[3
]}

Lo Cascio, Patrizia ^{[4
]}

Zentilin, Lorena ^{[5
]}

Giacca, Mauro ^{[5
]}

Squadrito, Francesco ^{[1
]}

机构：

[1] Univ Messina, Dept Clin & Expt Med & Pharmacol, Pharmacol Sect, Messina, Italy

[2] Univ Messina, Dept Surg Sci, Messina, Italy

[3] Univ Messina, Sect Vet Pharmacol & Toxicol, Dept Vet Publ Hlth, Messina, Italy

[4] Univ Messina, Fac Sci, Dept Anim Biol & Marine Ecol, Messina, Italy

[5] Int Ctr Genet Engn & Biotechnol, Mol Med Lab, I-34012 Trieste, Italy

来源：

CLINICAL SCIENCE | 2008年 / 114卷 / 11-12期

关键词：

angiogenesis; angiopoietin-1 (Ang-1); diabetes; eNOS (endothelial NO synthase); VEGF (vascular endothelial growth factor); wound healing;

D O I：

10.1042/CS20070250

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 [基础医学];

摘要：

Ang-1 (angiopoietin-1) improves the ineffective angiogenesis and impaired wound healing in diabetes; however, the mechanism underlying this positive effect is still far from being completely understood. In the present study, we investigated whether rAAV (recombinant adeno-associated virus)-Ang-1 gene transfer could improve wound repair in genetically diabetic mice (db(+)/db(+)) and the mechanism(s) by which it causes new vessel formation. An incisional skin-wound model in diabetic and normoglycaemic mice was used. After the incision, animals received rAAV-LacZ or rAAV-Ang-1 in the wound edge. After 7 and 14 days, wounds were used to (i) confirm Ang-1 gene transfer, (ii) assess histologically the healing process, (iii) evaluate wound-breaking strength, and (iv) study new vessel formation by PECAM-1 (platelet/endothelial cell adhesion molecule-1) immunostaining. Finally, we investigated VEGF (vascular endothelial growth factor) mRNA and protein levels, eNOS (endothelial NO synthase) expression and VEGFR-1 and VEGFR-2 (VEGF receptor-1 and -2 respectively) immunostaining. The efficiency of Ang-1 gene transfer was confirmed by increased mRNA and protein expression of the protein. rAAV-Ang-1 significantly improved the healing process, stimulating re-epithelization and collagen maturation, increasing breaking strength and significantly augmenting the number of new vessels, as indicated by PECAM-1 immunostaining. However, Ang-1 gene transfer did not modify the decrease in VEGF mRNA and protein expression in diabetic mice; in contrast, Ang-1 increased eNOS expression and augmented nitrate wound content and VEGFR-2 immunostaining and protein expression. Ang-1 gene transfer did not change vascular permeability. Similar results were obtained in normoglycaemic animals. In conclusion, our results provide strong evidence that Ang-1 gene transfer improves the delayed wound repair in diabetes by inducing angiogenesis in a VEGF-independent manner.

引用

页码：707 / 718

页数：12

共 25 条

[1]

Inhibition of lipid peroxidation restores impaired vascular endothelial growth factor expression and stimulates wound healing and angiogenesis in the genetically diabetic mouse [J].