Nicotinamide mononucleotide restores impaired metabolism, endothelial cell proliferation and angiogenesis in old sedentary male mice
Kevin Kiesworo,
Thomas Agius,
Michael R. Macarthur,
Martine Lambelet,
Arnaud Lyon,
Jing Zhang,
Guillermo Turiel,
Zheng Fan,
Sènan d’Almeida,
Korkut Uygun,
Heidi Yeh,
Sébastien Déglise,
Katrien de Bock,
Sarah J. Mitchell,
Alejandro Ocampo,
Florent Allagnat,
Alban Longchamp
Affiliations
Kevin Kiesworo
Department of Vascular Surgery, Lausanne University Hospital (CHUV), Lausanne, Switzerland
Thomas Agius
Department of Vascular Surgery, Lausanne University Hospital (CHUV), Lausanne, Switzerland
Michael R. Macarthur
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA; Ludwig Princeton Branch, Princeton University, Princeton, NJ, USA
Martine Lambelet
Department of Vascular Surgery, Lausanne University Hospital (CHUV), Lausanne, Switzerland
Arnaud Lyon
Transplantation Centre and Transplantation Immunopathology Laboratory, Department of Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland
Jing Zhang
Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
Guillermo Turiel
Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
Zheng Fan
Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Heidi Yeh
Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Sébastien Déglise
Department of Vascular Surgery, Lausanne University Hospital (CHUV), Lausanne, Switzerland
Katrien de Bock
Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
Sarah J. Mitchell
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA; Ludwig Princeton Branch, Princeton University, Princeton, NJ, USA
Alejandro Ocampo
Department of Biomedical Sciences, Lausanne University (UNIL), Lausanne, Switzerland
Florent Allagnat
Department of Vascular Surgery, Lausanne University Hospital (CHUV), Lausanne, Switzerland
Alban Longchamp
Department of Vascular Surgery, Lausanne University Hospital (CHUV), Lausanne, Switzerland; Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Corresponding author
Summary: 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 13C 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+ 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+-dependent metabolism in the maintenance of EC proliferation capacity with age, and the therapeutic potential of NAD precursors.
