title: Low-dosage inhibition of Dll4 signaling promotes wound healing by inducing functional neo-angiogenesis.
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.
authors.affiliation: Centro Interdisciplinar de Investigação em Sanidade Animal (CIISA), Lisbon Technical University, Lisbon, Portugal.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Trindade
authors.forename: Dusan
authors.initials: D
authors.lastname: Djokovic
authors.forename: Joana
authors.initials: J
authors.lastname: Gigante
authors.forename: Marina
authors.initials: M
authors.lastname: Badenes
authors.forename: Ana-Rita
authors.initials: AR
authors.lastname: Pedrosa
authors.forename: Ana-Carina
authors.initials: AC
authors.lastname: Fernandes
authors.forename: Luís
authors.initials: L
authors.lastname: Lopes-da-Costa
authors.forename: Valery
authors.initials: V
authors.lastname: Krasnoperov
authors.forename: Ren
authors.initials: R
authors.lastname: Liu
authors.forename: Parkash S
authors.initials: PS
authors.lastname: Gill
authors.forename: António
authors.initials: A
authors.lastname: Duarte
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism; D002135:Calcium-Binding Proteins; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D012038:Regeneration / Q000187:drug effects; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D012867:Skin / Q000098:blood supply* / Q000187:drug effects / Q000503:physiopathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040321:Vascular Endothelial Growth Factor Receptor-3; C519665:DLL4 protein, mouse; C571158:Dll4-Fc protein; C485778:Hey2 protein, mouse