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CD47 promotes age-associated deterioration in angiogenesis, blood flow and glucose homeostasis

  • Ghimire, Kedar Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, 176 Hawkesbury Rd, Sydney 2145, NSW, Australia - Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, BST Starzl Tower, 200 Lothrop Street, Pittsburgh, PA 15261, USA
  • Li, Yao Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, BST Starzl Tower, 200 Lothrop Street, Pittsburgh, PA 15261, USA - Department of Pharmacology & Chemical Biology, University of Pittsburgh, BST Starzl Tower, 200 Lothrop Street, Pittsburgh, PA 15261, USA
  • Chiba, Takuto Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, BST Starzl Tower, 200 Lothrop Street, Pittsburgh, PA 15261, USA
  • Julovi, Sohel M. Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, 176 Hawkesbury Rd, Sydney 2145, NSW, Australia
  • Li, Jennifer Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, 176 Hawkesbury Rd, Sydney 2145, NSW, Australia
  • Ross, Mark A. Center for Biologic Imaging, University of Pittsburgh School of Medicine, BST, 200 Lothrop Street, Pittsburgh, PA 15261, USA
  • Straub, Adam C. Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, BST Starzl Tower, 200 Lothrop Street, Pittsburgh, PA 15261, USA - Department of Pharmacology & Chemical Biology, University of Pittsburgh, BST Starzl Tower, 200 Lothrop Street, Pittsburgh, PA 15261, USA
  • O’Connell, Philip J. Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, 176 Hawkesbury Rd, Sydney 2145, NSW, Australia
  • Rüegg, Curzio Department of Oncology, Microbiology and Immunology, Faculty of Sciences and Medicine, University of Fribourg, Chemin du Musée 18, PER 17, 1700 Fribourg, Switzerland
  • Pagano, Patrick J. Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, BST Starzl Tower, 200 Lothrop Street, Pittsburgh, PA 15261, USA - Department of Pharmacology & Chemical Biology, University of Pittsburgh, BST Starzl Tower, 200 Lothrop Street, Pittsburgh, PA 15261, USA
  • Isenberg, Jeffrey S. Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, BST Starzl Tower, 200 Lothrop Street, Pittsburgh, PA 15261, USA - Department of Medicine, University of Pittsburgh, BST Starzl Tower, 200 Lothrop Street, Pittsburgh, PA 15261, USA
  • Rogers, Natasha M. Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, 176 Hawkesbury Rd, Sydney 2145, NSW, Australia - Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, BST Starzl Tower, 200 Lothrop Street, Pittsburgh, PA 15261, USA
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    15.07.2020
Published in:
  • Cells. - 2020, vol. 9, no. 7, p. 1695
English The aged population is currently at its highest level in human history and is expected to increase further in the coming years. In humans, aging is accompanied by impaired angiogenesis, diminished blood flow and altered metabolism, among others. A cellular mechanism that impinges upon these manifestations of aging can be a suitable target for therapeutic intervention. Here we identify cell surface receptor CD47 as a novel age-sensitive driver of vascular and metabolic dysfunction. With the natural aging process, CD47 and its ligand thrombospondin-1 were increased, concurrent with a reduction of self-renewal transcription factors OCT4, SOX2, KLF4 and cMYC (OSKM) in arteries from aged wild-type mice and older human subjects compared to younger controls. These perturbations were prevented in arteries from aged CD47-null mice. Arterial endothelial cells isolated from aged wild-type mice displayed cellular exhaustion with decreased proliferation, migration and tube formation compared to cells from aged CD47-null mice. CD47 suppressed ex vivo sprouting, in vivo angiogenesis and skeletal muscle blood flow in aged wild-type mice. Treatment of arteries from older humans with a CD47 blocking antibody mitigated the age-related deterioration in angiogenesis. Finally, aged CD47-null mice were resistant to age- and diet-associated weight gain, glucose intolerance and insulin desensitization. These results indicate that the CD47-mediated signaling maladapts during aging to broadly impair endothelial self-renewal, angiogenesis, perfusion and glucose homeostasis. Our findings provide a strong rationale for therapeutically targeting CD47 to minimize these dysfunctions during aging.
Faculty
Faculté des sciences et de médecine
Department
Médecine 3ème année
Language
  • English
Classification
Biology
License
License undefined
Identifiers
Persistent URL
https://folia.unifr.ch/unifr/documents/308921
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