Significance: Re-establishment of a functional vascular network is a critical component of successful wound repair. One of the most potent pro-angiogenic agents is vascular endothelial growth factor (VEGF), which, from a basic science and pre-clinical perspective, seems ideal for the therapeutic stimulation of blood vessel growth in non-healing wounds.

Critical Issues: Current strategies to improve the dysfunctional angiogenesis that occurs in non-healing wounds are inadequate with regard to the nature and magnitude of the clinical problem. However, VEGF therapy has so far been unsuccessful in promoting healing in the clinic. More effective means of delivery to the wound, which take into account the biochemical and spatio-temporal aspects of angiogenesis, may be necessary to realize VEGF's therapeutic potential. Reviewed approaches for the regulation of wound angiogenesis include: targeting regulators of intracellular VEGF signaling, making use of collagen-binding VEGF fusion proteins for increased retention in the wound, and implantation of heterogeneous scaffold systems for spatial control of angiogenesis with simultaneous use of VEGF and its inhibitor.

Future Directions: To maximize efficacy of therapeutic VEGF, it may be necessary to also target its intracellular inhibitory mechanisms. Immobilizing VEGF to the wound matrix may increase its bioavailability and therapeutic efficacy. Gaining spatial control of angiogenesis opens up possibilities for advanced directed therapy. The reviewed studies present innovative approaches to in vivo directed modulation of angiogenesis utilizing VEGF biology which can, if taken further and validated in human subjects, have significant impact on clinical wound care in the future.