NAD-dependent redox control enables endothelial quiescence and vascular stabilization during angiogenesis

  • Cell Metab. 2026 Apr 29:S1550-4131(26)00142-7. doi: 10.1016/j.cmet.2026.04.004.
Wencao Zhao  1 ,  Wenkai Zhu  2 ,  Trace Thome  1 ,  Ioana Soaita  1 ,  Jae Woo Jung  1 ,  Michael C Noji  1 ,  Jian Li  1 ,  Huajun Bai  3 ,  Yansen Xiao  4 ,  Yifan Yang  1 ,  Chelsea Thorsheim  1 ,  Wei Zhou  1 ,  Yijun Yang  1 ,  Kristina Li  2 ,  Jonathan J Edwards  5 ,  Ivan A Kuznetsov  1 ,  Boa Kim  6 ,  Joseph A Baur  7 ,  Zoltan Arany  8
Affiliations
  • 1. Department of Medicine, Cardiovascular Institute, Institute of Diabetes Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 2. Department of Medicine, Cardiovascular Institute, Institute of Diabetes Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA.
  • 3. Center for Mitochondrial and Epigenomic Medicine, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 4. Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 5. Department of Medicine, Cardiovascular Institute, Institute of Diabetes Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Pediatrics, Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 6. Department of Pathology and Laboratory Medicine, McAllister Heart Institute, Nutrition Obesity Research Center, Lineberger Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
  • 7. Department of Physiology, Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 8. Department of Medicine, Cardiovascular Institute, Institute of Diabetes Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: [email protected].
PMID: 42061402 DOI: 10.1016/j.cmet.2026.04.004
Abstract

Angiogenesis requires endothelial cells (ECs) to toggle between quiescence versus proliferation, migration, and invasion. While activation from quiescence is well characterized, mechanisms governing the return from proliferation to quiescence (PtoQ) remain unclear. We show here that metabolic rewiring during PtoQ renders ECs sensitive to oxidative stress, requiring nicotinamide adenine dinucleotide (NAD) turnover for protection. Limiting EC NAD does not affect proliferation or migration but prevents cell-cell contact formation and quiescence acquisition during PtoQ. In vivo and ex vivo, limiting EC NAD permits initial sprouting but impairs vascular stabilization and plexus formation. Mechanistically, NAD suppresses mitochondria-derived hydrogen peroxide (H2O2) during PtoQ. Exogenous H2O2 mimics NAD deficiency, whereas its removal rescues PtoQ. In pathological settings, inhibiting NAD synthesis limits exuberant angiogenesis of retinopathy and tumors. In summary, we unveil metabolic events critical for PtoQ, a poorly studied component of angiogenesis, and point to new ways to suppress pathological angiogenesis.

Keywords
H(2)O(2); NAD; NADPH; NAMPT; angiogenesis; endothelial cells; metabolism; quiescence.
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