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Topical vascular endothelial growth factor reverses delayed wound healing secondary to angiogenesis inhibitor
Joseph Michaels1, Michael Dobryansky, Robert D Galiano
1Laboratory of Microvascular Research and Vascular Tissue Engineering, Institute of Reconstructive Plastic Surgery, New York University Medical Center, New York 10016, USA.
Abstract:
The prevention of new blood vessel growth is an increasingly attractive strategy to limit tumor growth. However, it remains unclear whether anti-angiogenesis approaches will impair wound healing, a process thought to be angiogenesis dependent. Results of previous studies differ as to whether angiogenesis inhibitors delay wound healing. We evaluated whether endostatin at tumor-inhibiting doses delayed excisional wound closure. C57/BL6J mice were treated with endostatin or phosphate-buffered solution 3 days prior to the creation of two full-thickness wounds on the dorsum. Endostatin was administered daily until wound closure was complete. A third group received endostatin, but also had daily topical vascular endothelial growth factor applied locally to the wound. Wound area was measured daily and the wounds were analyzed for granulation tissue formation, epithelial gap, and wound vascularity. Endostatin-treated mice showed a significant delay in wound healing. Granulation tissue formation and wound vascularity were significantly decreased, but reepithelialization was not effected. Topical vascular endothelial growth factor application to wounds in endostatin-treated mice resulted in increased granulation tissue formation, increased wound vascularity, and wound closure approaching that of control mice. This study shows that the angiogenesis inhibitor endostatin delays wound healing and that topical vascular endothelial growth factor is effective in counteracting this effect.
Insights
Anti-angiogenesis therapy with endostatin significantly delays wound healing by reducing vascularity. However, topical vascular endothelial growth factor application can effectively counteract this delay, promoting wound closure.
Area of Science:
- Oncology
- Wound Healing Research
- Vascular Biology
Background:
- Tumor growth can be limited by preventing new blood vessel growth (angiogenesis).
- The impact of anti-angiogenesis strategies on wound healing, which relies on angiogenesis, is not fully understood.
- Previous studies have yielded conflicting results regarding angiogenesis inhibitors and wound healing.
Purpose of the Study:
- To investigate whether endostatin, an angiogenesis inhibitor used at tumor-inhibiting doses, delays excisional wound closure in mice.
- To determine if topical vascular endothelial growth factor (VEGF) can overcome any delay in wound healing caused by endostatin.
Main Methods:
- C57/BL6J mice received daily endostatin injections or a placebo before and after wound creation.
- A subset of endostatin-treated mice received daily topical VEGF application to their wounds.
- Wound closure, granulation tissue formation, epithelial gap, and vascularity were assessed daily.
Main Results:
- Endostatin treatment significantly delayed wound healing compared to controls.
- Granulation tissue formation and wound vascularity were significantly reduced in endostatin-treated mice.
- Reepithelialization was not affected by endostatin, but topical VEGF application restored granulation tissue, vascularity, and accelerated wound closure.
Conclusions:
- The angiogenesis inhibitor endostatin delays wound healing.
- Topical VEGF is effective in counteracting the wound healing delay induced by endostatin.
- These findings highlight the critical role of angiogenesis in wound repair and suggest therapeutic strategies for managing anti-angiogenic effects.
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