COMP-angiopoietin 1 Gene Transfer Enhances Cutaneous Wound Healing: DISCUSSION
The angiogenic effect of Ang 1 has been reported in previous studies. Ang 1 and Tie 2-deficient mice had similar phenotypes that were characterized by embryonic lethality with severe vascular remodeling defects, insufficient vessel stabilization and perturbed vascular maturation. Promoted angio- genesis has been reported on for transgenic mice that overexpress Ang 1 in the skin. In addition, there have been reports that exogenous and localized Ang 1 treatment with naked DNA-mediated or adenovirus-mediated Ang 1 enhanced angiogenesis in the gastric ulcer model or the skin flap model.
In this study, we wanted to verify whether a systemic adenovirus-associated COMP-Ang 1 treatment can induce angiogenesis in a cutaneous wound healing model. Our results demonstrated that angiogenesis in the COMP-Ang 1 treated group was significantly increased at day 3, 7 and 14, compared with the control group. Although we did not confirm the expression of COMP-Ang 1 either in the plasma or in the cutaneous wound after systemic injection, the level of systemic circulating COMP-Ang 1 is known to be increased as early as 12 hours after Ade-COMP-Ang 1 injection, peaking at 1 to 2 weeks and gradually declining thereafter. The levels return to the control levels at 6 weeks after systemic treatment in the murine model. Therefore, we could infer that the enhanced angiogenesis in the COMP-Ang 1 treated group is attributable to the increased level of COMP-Ang 1 in the plasma.
The results of this study showed that adenovirus mediated COMP-Ang 1 therapy significantly enhanced the reduction of wound size at day 3 and 7 after wound surgery; however, there was no significant difference at day 14. These data coincided with previous reports showing the difference of the reduction of the wound size did not reach statistical significance after day 7 or 9 after wounding, in an adenovirus-mediated VEGF treatment model or a cultured autologous fibroblast transplant model, respectively.
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A recent explosion of newly discovered growth factors that act on the vascular endothelium has coincided with the application of powerful new genetic approaches to the problem of vascular development. The vascular endothelium-specific growth factors include five members of the VEGF family, four members of the Ang family, and at least one member of the large ephrin family. In addition, many other growth factors that are not vascular endothelium-specific are also required for blood vessel formation, and these include the members of the platelet-derived growth factor families or the transforming growth factor families. However, the critical roles on many other systems of the latter limit their clinical application. VEGF has been the most commonly studied and used growth factor for promoting wound healing. The previous studies have shown that VEGF is a more potent growth factor for endothelial proliferation than is Ang 1.
