Abstract
Recent findings regarding Dll4 function in physiological and pathological conditions indicate that this Notch ligand may constitute an important therapeutic target. Dll4 appears to be a major anti-angiogenic agent, occupying a central role in various angiogenic pathways. The first trials of anti-Dll4 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 Dll4 function is known to be closely dependent on expression levels, we envisioned that the therapeutic anti-Dll4 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 Dll4/Notch signaling causes improved vascular function and accelerated wound healing.
Highlights
Wound healing is a physiological process required for maintenance of an intact skin barrier
Wound healing was delayed in eDll4lox/lox mice (Fig. 1D), which was statistically significant at day 2 and persisted
The importance of Dll4 was first described by its function in the establishment of endothelial identity and in the regulation of vascular morphogenesis in embryonic vascular development
Summary
Wound healing is a physiological process required for maintenance of an intact skin barrier. Angiogenesis, the growth of new blood vessels, is an important natural process required for healing wounds and for restoring blood flow to tissues after injury or insult [1]. Angiogenesis is initiated by multiple molecular signals, including hemostatic factors, inflammation, cytokine growth factors, and cell-matrix interactions, and is mediated throughout the entire wound-healing process [2,3]. New blood vessels grow via a cascade of biological events to form granulation tissue in the wound bed [4]. This process is sustained until the terminal stages of healing, when angiogenesis is slowed by reduced levels of growth factors, resolution of inflammation, stabilized tissue matrix, and endogenous inhibitors of angiogenesis [2,3]. Defects in the angiogenesis pathway impair granulation and delay healing [4]
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