Mechanism of sustained release of vascular endothelial growth factor in accelerating experimental diabetic healing.
In this study, we hypothesize that local sustained release of vascular endothelial growth factor (VEGF), using adenovirus vector (ADV)-mediated gene transfer, accelerates experimental wound healing. This hypothesis was tested by determining the specific effects of VEGF(165) application on multiple aspects of the wound healing process, that is, time to complete wound closure and skin biomechanical properties. After showing accelerated wound healing in vivo, we studied the mechanism to explain the findings on multiple aspects of the wound healing cascade, including epithelialization, collagen deposition, and cell migration. Intradermal treatment of wounds in non-obese diabetic and db/db mice with ADV/VEGF(165) improves healing by enhancing tensile stiffness and/or increasing epithelialization and collagen deposition, as well as by decreasing time to wound closure. VEGF(165), in vitro, stimulates the migration of cultured human keratinocytes and fibroblasts, thus revealing a non-angiogenic effect of VEGF on wound closure. In conclusion, ADV/VEGF is effective in accelerating wound closure by stimulating angiogenesis, epithelialization, and collagen deposition. In the future, local administration and sustained, controlled release of VEGF(165) may decrease amputations in patients with diabetic foot ulcers and possibly accelerate closure of venous ulcers and pressure ulcers.
Brem
Harold
H
Helen and Martin Kimmel Wound Center, Division of Wound Healing & Regenerative Medicine, Department of Surgery, New York University, New York, New York 10016, USA. Harold.brem@nyumc.org
Kodra
Arber
A
Golinko
Michael S
MS
Entero
Hyacinth
H
Stojadinovic
Olivera
O
Wang
Vincent M
VM
Sheahan
Claudia M
CM
Weinberg
Alan D
AD
Woo
Savio L C
SL
Ehrlich
H Paul
HP
Tomic-Canic
Marjana
M
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D003094:Collagen / Q000378:metabolism; D003920:Diabetes Mellitus / Q000503:physiopathology / Q000628:therapy*; D004848:Epithelium / Q000502:physiology; D005260:Female; D015316:Genetic Therapy; D006097:Granulation Tissue / Q000378:metabolism; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D012038:Regeneration; D013718:Tensile Strength; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology*
C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D003094:Collagen