title: Inhibition of Notch signaling by Dll4-Fc promotes reperfusion of acutely ischemic tissues.
abstract: Notch pathway regulates vessel development and maturation. Dll4, a high-affinity ligand for Notch, is expressed predominantly in the arterial endothelium and is induced by hypoxia among other factors. Inhibition of Dll4 has paradoxical effects of reducing the maturation and perfusion in newly forming vessels while increasing the density of vessels. We hypothesized that partial and/or intermittent inhibition of Dll4 may lead to increased vascular response and still allow vascular maturation to occur. Thus tissue perfusion can be restored rapidly, allowing quicker recovery from ischemia or tissue injury. Our studies in two different models (hindlimb ischemia and skin flap) show that inhibition of Dll4 at low dose allows faster recovery from vascular and tissue injury. This opens a new possibility for Dll4 blockade's therapeutic application in promoting recovery from vascular injury and restoring blood supply to ischemic tissues.
authors.affiliation: Department of Pathology, University of Southern California, Los Angeles, USA.
authors.forename: Ren
authors.initials: R
authors.lastname: Liu
authors.forename: Alexandre
authors.initials: A
authors.lastname: Trindade
authors.forename: Zhanfeng
authors.initials: Z
authors.lastname: Sun
authors.forename: Ram
authors.initials: R
authors.lastname: Kumar
authors.forename: Fred A
authors.initials: FA
authors.lastname: Weaver
authors.forename: Valery
authors.initials: V
authors.lastname: Krasnoperov
authors.forename: Kranthi
authors.initials: K
authors.lastname: Naga
authors.forename: Antonio
authors.initials: A
authors.lastname: Duarte
authors.forename: Parkash S
authors.initials: PS
authors.lastname: Gill
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000187:drug effects; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D058752:Free Tissue Flaps / Q000098:blood supply; D006614:Hindlimb / Q000098:blood supply; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D007511:Ischemia / Q000188:drug therapy*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008817:Mice, Mutant Strains; D051880:Receptors, Notch / Q000037:antagonists & inhibitors*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D015424:Reperfusion; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000098:blood supply; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis
chemical_list: C571158:Dll4-Fc protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins; C064045:delta protein; D040301:Vascular Endothelial Growth Factor Receptor-2