Low-dosage inhibition of Dll4 signaling promotes wound healing by inducing functional neo-angiogenesis

• Published in: PloS one 2012-01, Vol.7 (1), p.e29863
• Main Authors: Trindade, Alexandre, Djokovic, Dusan, Gigante, Joana, Badenes, Marina, Pedrosa, Ana-Rita, Fernandes, Ana-Carina, Lopes-da-Costa, Luís, Krasnoperov, Valery, Liu, Ren, Gill, Parkash S, Duarte, António
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biology; Birth defects; Blood vessels; Blood Vessels - drug effects; Blood Vessels - metabolism; Clinical trials; Collaboration; Diabetes mellitus; Diabetics; Dosage; Dose-Response Relationship, Drug; Drug dosages; Endothelium; Female; Gene Expression Regulation - drug effects; Health aspects; Hypoxia; Immunohistochemistry; Inhibition; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Ligands; Male; Medicine; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Morphogenesis; Motility; Notch protein; Perfusion; Physiological aspects; Physiology; Recombinant Fusion Proteins - pharmacology; Regeneration - drug effects; Repressor Proteins - genetics; Repressor Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - drug effects; Signal Transduction - genetics; Signal Transduction - physiology; Signaling; Skin - blood supply; Skin - drug effects; Skin - physiopathology; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-1 - genetics; Vascular Endothelial Growth Factor Receptor-1 - metabolism; Vascular Endothelial Growth Factor Receptor-3 - genetics; Vascular Endothelial Growth Factor Receptor-3 - metabolism; Veins & arteries; Wound care; Wound healing; Wound Healing - drug effects; Wound Healing - genetics; Wound Healing - physiology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0029863

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.