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Dll4-Notch signaling determines the formation of native arterial collateral networks and arterial function in mouse ischemia models

Item Type:Article
Title:Dll4-Notch signaling determines the formation of native arterial collateral networks and arterial function in mouse ischemia models
Creators Name:Cristofaro, B. and Shi, Y. and Faria, M. and Suchting, S. and Leroyer, A.S. and Trindade, A. and Duarte, A. and Zovein, A.C. and Iruela-Arispe, M.L. and Nih, L.R. and Kubis, N. and Henrion, D. and Loufrani, L. and Todiras, M. and Schleifenbaum, J. and Gollasch, M. and Zhuang, Z.W. and Simons, M. and Eichmann, A. and le Noble, F.
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.
Keywords:Angiogenesis, Arteriogenesis, Vessel Branching, Dll4-Notch Signaling, Animals, Mice
Publisher:Company of Biologists
Page Range:1720-1729
Date:April 2013
Official Publication:https://doi.org/10.1242/dev.092304
PubMed:View item in PubMed

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