title: Dll4-Notch signaling determines the formation of native arterial collateral networks and arterial function in mouse ischemia models.
abstract: Arteriogenesis requires growth of pre-existing arteriolar collateral networks and determines clinical outcome in arterial occlusive diseases. Factors responsible for the development of arteriolar collateral networks are poorly understood. The Notch ligand Delta-like 4 (Dll4) promotes arterial differentiation and restricts vessel branching. We hypothesized that Dll4 may act as a genetic determinant of collateral arterial networks and functional recovery in stroke and hind limb ischemia models in mice. Genetic loss- and gain-of-function approaches in mice showed that Dll4-Notch signaling restricts pial collateral artery formation by modulating arterial branching morphogenesis during embryogenesis. Adult Dll4(+/-) mice showed increased pial collateral numbers, but stroke volume upon middle cerebral artery occlusion was not reduced compared with wild-type littermates. Likewise, Dll4(+/-) mice showed reduced blood flow conductance after femoral artery occlusion, and, despite markedly increased angiogenesis, tissue ischemia was more severe. In peripheral arteries, loss of Dll4 adversely affected excitation-contraction coupling in arterial smooth muscle in response to vasopressor agents and arterial vessel wall adaption in response to increases in blood flow, collectively contributing to reduced flow reserve. We conclude that Dll4-Notch signaling modulates native collateral formation by acting on vascular branching morphogenesis during embryogenesis. Dll4 furthermore affects tissue perfusion by acting on arterial function and structure. Loss of Dll4 stimulates collateral formation and angiogenesis, but in the context of ischemic diseases such beneficial effects are overruled by adverse functional changes, demonstrating that ischemic recovery is not solely determined by collateral number but rather by vessel functionality.
authors.affiliation: CIRB Collège de France, Inserm U1050/CNRS UMR 7241, Paris, France.
authors.forename: Brunella
authors.initials: B
authors.lastname: Cristofaro
authors.forename: Yu
authors.initials: Y
authors.lastname: Shi
authors.forename: Marcella
authors.initials: M
authors.lastname: Faria
authors.forename: Steven
authors.initials: S
authors.lastname: Suchting
authors.forename: Aurelie S
authors.initials: AS
authors.lastname: Leroyer
authors.forename: Alexandre
authors.initials: A
authors.lastname: Trindade
authors.forename: Antonio
authors.initials: A
authors.lastname: Duarte
authors.forename: Ann C
authors.initials: AC
authors.lastname: Zovein
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Iruela-Arispe
authors.forename: Lina R
authors.initials: LR
authors.lastname: Nih
authors.forename: Nathalie
authors.initials: N
authors.lastname: Kubis
authors.forename: Daniel
authors.initials: D
authors.lastname: Henrion
authors.forename: Laurent
authors.initials: L
authors.lastname: Loufrani
authors.forename: Mihail
authors.initials: M
authors.lastname: Todiras
authors.forename: Johanna
authors.initials: J
authors.lastname: Schleifenbaum
authors.forename: Maik
authors.initials: M
authors.lastname: Gollasch
authors.forename: Zhen W
authors.initials: ZW
authors.lastname: Zhuang
authors.forename: Michael
authors.initials: M
authors.lastname: Simons
authors.forename: Anne
authors.initials: A
authors.lastname: Eichmann
authors.forename: Ferdinand
authors.initials: F
authors.lastname: le Noble
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000704:Analysis of Variance; D000818:Animals; D002135:Calcium-Binding Proteins; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007511:Ischemia / Q000378:metabolism / Q000503:physiopathology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D055806:Microvessels / Q000196:embryology* / Q000502:physiology; D009024:Morphogenesis / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D051880:Receptors, Notch / Q000378:metabolism*; D012039:Regional Blood Flow / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D055114:X-Ray Microtomography
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch