Nicotinamide mononucleotide restores impaired metabolism, endothelial cell proliferation and angiogenesis in old sedentary male mice
Aging is accompanied by a decline in neovascularization potential and increased susceptibility to ischemic injury. Here, we confirm the age-related impaired neovascularization following ischemic leg injury and impaired angiogenesis. The age-related deficits in angiogenesis arose primarily from diminished EC proliferation capacity, but not migration or VEGF sensitivity. Aged EC harvested from the mouse skeletal muscle displayed a pro-angiogenic gene expression phenotype, along with considerable changes in metabolic genes. Metabolomics analysis and <sup>13</sup>C glucose tracing revealed impaired ATP production and blockade in glycolysis and TCA cycle in late passage HUVECs, which occurred at nicotinamide adenine dinucleotide (NAD⁺)-dependent steps, along with NAD<sup>+</sup> depletion. Supplementation with nicotinamide mononucleotide (NMN), a precursor of NAD⁺, enhances late-passage EC proliferation and sprouting angiogenesis from aged mice aortas. Taken together, our study illustrates the importance of NAD<sup>+</sup>-dependent metabolism in the maintenance of EC proliferation capacity with age, and the therapeutic potential of NAD precursors.
Authors
- Eleanor Mitchell (ORCID: https://orcid.org/0000-0002-6998-4533)
- Zheng Fan (ORCID: https://orcid.org/0000-0003-1934-2521)
- Guillermo Turiel (ORCID: https://orcid.org/0009-0007-9650-1553)
- Heidi Yeh (ORCID: https://orcid.org/0000-0002-7379-0600)
- Arnaud Lyon (ORCID: https://orcid.org/0000-0003-1781-330X)
- Thomas Agius (ORCID: https://orcid.org/0000-0001-6917-0831)
- Katrien De Bock (ORCID: https://orcid.org/0000-0001-8232-4663)
- Sébastien Déglise (ORCID: https://orcid.org/0000-0001-8244-952X)
- Alban Longchamp (ORCID: https://orcid.org/0000-0002-1743-4935)
- Kevin Kiesworo
- Korkut Uygun
- Michael R. MacArthur (ORCID: https://orcid.org/0000-0003-3593-6995)
- Martine Lambelet (ORCID: https://orcid.org/0000-0002-4239-2554)
- Florent Allagnat (ORCID: https://orcid.org/0000-0001-6528-679X)
- Sènan Mickaël D'Almeida (ORCID: https://orcid.org/0000-0002-0247-298X)
- Alejandro Ocampo (ORCID: https://orcid.org/0000-0002-3731-3647)
- Jing Zhang (ORCID: https://orcid.org/0000-0002-6566-6693)
Institutions
- Harvard University (US)
- Princeton University (US)
- Centre Hospitalier Universitaire Vaudois (CH)
- ETH Zurich (CH)
- Massachusetts General Hospital (US)
- Lausanne Natation (CH)
- École Polytechnique Fédérale de Lausanne (CH)
- University of Lausanne (CH)
Publication Details
- Journal
- iScience
- Published
- 2024-12-20
- DOI
- https://doi.org/10.1016/j.isci.2024.111656
- Citations
- 8
- Primary Topic
- Sirtuins and Resveratrol in Medicine
- Type
- article
- Field-Weighted Citation Impact
- 2.75
Funders
- National Science Foundation
- Novartis Foundation
- École Polytechnique Fédérale de Lausanne
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Novartis Stiftung für Medizinisch-Biologische Forschung
- Fondation Leenaards
- Université de Lausanne
- Fondation Pierre Mercier pour la Science