Low-Dosage Inhibition of DII4 Signaling Promotes Wound Healing by Inducing Functional Neo-Angiogenesis

Recent findings regarding DII4 function in physiological and pathological conditions indicate that this Notch ligand may constitute an important therapeutic target. DII4 appears to be a major anti-angiogenic agent, occupying a central role in various angiogenic pathways. The first trials of anti-DII4 therapy in mice demonstrated a paradoxical effect, as it reduced tumor perfusion and growth despite leading to an increase in vascular density. This is seen as the result of insufficient maturation of the newly formed vasculature causing a circulatory defect and increased tumor hypoxia. As DII4 function is known to be closely dependent on expression levels, we envisioned that the therapeutic anti-DII4 dosage could be modulated to result in the increase of adequately functional blood vessels. This would be useful in conditions where vascular function is a limiting factor for recovery, like wound healing and tissue hypoxia, especially in diabetic patients. Our experimental results in mice confirmed this possibility, revealing that low dosage inhibition of DII4/Notch signaling causes improved vascular function and accelerated wound healing.