title: Endothelial Shc regulates arteriogenesis through dual control of arterial specification and inflammation via the notch and nuclear factor-κ-light-chain-enhancer of activated B-cell pathways.
abstract: BACKGROUND
  Arteriogenesis, the shear stress-driven remodeling of collateral arteries, is critical in restoring blood flow to ischemic tissue after a vascular occlusion. Our previous work has shown that the adaptor protein Shc mediates endothelial responses to shear stress in vitro.
  
  
  OBJECTIVE
  To examine the role of the adaptor protein Shc in arteriogenesis and endothelial-dependent responses to shear stress in vivo.
  
  
  RESULTS
  Conditional knockout mice in which Shc is deleted from endothelial cells were subjected to femoral artery ligation. Hindlimb perfusion recovery was attenuated in Shc conditional knockout mice compared with littermate controls. Reduced perfusion was associated with blunted collateral remodeling and reduced capillary density. Bone marrow transplantation experiments revealed that endothelial Shc is required for perfusion recovery because loss of Shc in bone marrow-derived hematopoietic cells had no effect on recovery. Mechanistically, Shc deficiency resulted in impaired activation of the nuclear factor κ-light-chain-enhancer of activated B-cell-dependent inflammatory pathway and reduced CD45⁺ cell infiltration. Unexpectedly, Shc was required for arterial specification of the remodeling arteriole by mediating upregulation of the arterial endothelial cell marker ephrinB2 and activation of the Notch pathway. In vitro experiments confirmed that Shc was required for shear stress-induced activation of the Notch pathway and downstream arterial specification through a mechanism that involves upregulation of Notch ligands delta-like 1 and delta-like 4.
  
  
  CONCLUSIONS
  Shc mediates activation of 2 key signaling pathways that are critical for inflammation and arterial specification; collectively, these pathways contribute to arteriogenesis and the recovery of blood perfusion.
authors: Curriculum in Genetics & Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.
authors: Daniel T
authors: DT
authors: Sweet
authors: Department of Cell & Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.
authors: Zhongming
authors: Z
authors: Chen
authors: Department of Cell & Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.
authors: Christopher S
authors: CS
authors: Givens
authors: Department of Medicine, Division of Hematology and Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.
authors: A Phillip
authors: AP
authors: Owens
authors: McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.
authors: Mauricio
authors: M
authors: Rojas
authors: Curriculum in Genetics & Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.|Department of Cell & Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.|McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.
authors: Ellie
authors: E
authors: Tzima
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001167:Arteritis / Q000209:etiology* / Q000235:genetics; D016026:Bone Marrow Transplantation; D002135:Calcium-Binding Proteins; D002448:Cell Adhesion; D003097:Collateral Circulation; D042783:Endothelial Cells / Q000378:metabolism; D036388:Ephrin-B2 / Q000502:physiology; D005263:Femoral Artery / Q000601:surgery; D005813:Genes, Synthetic; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D018056:Hemorheology; D006614:Hindlimb / Q000098:blood supply; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D007511:Ischemia / Q000503:physiopathology*; D007962:Leukocytes / Q000502:physiology; D008026:Ligation; D008297:Male; D008465:Mechanoreceptors / Q000502:physiology; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000235:genetics*; D051880:Receptors, Notch / Q000502:physiology*; D055765:Shc Signaling Adaptor Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D013314:Stress, Mechanical
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; C512925:Dlk1 protein, mouse; D036388:Ephrin-B2; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D016328:NF-kappa B; D051880:Receptors, Notch; D055765:Shc Signaling Adaptor Proteins
keywords: NF-κB; Notch; Shc; arteriogenesis; shear stress
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