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  • Review Article
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Mechanisms and consequences of endothelial cell senescence

Nature Reviews Cardiology volume 20, pages 38–51 (2023)Cite this article

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Abstract

Endothelial cells are located at the crucial interface between circulating blood and semi-solid tissues and have many important roles in maintaining systemic physiological function. The vascular endothelium is particularly susceptible to pathogenic stimuli that activate tumour suppressor pathways leading to cellular senescence. We now understand that senescent endothelial cells are highly active, secretory and pro-inflammatory, and have an aberrant morphological phenotype. Moreover, endothelial senescence has been identified as an important contributor to various cardiovascular and metabolic diseases. In this Review, we discuss the consequences of endothelial cell exposure to damaging stimuli (haemodynamic forces and circulating and endothelial-derived factors) and the cellular and molecular mechanisms that induce endothelial cell senescence. We also discuss how endothelial cell senescence causes arterial dysfunction and contributes to clinical cardiovascular diseases and metabolic disorders. Finally, we summarize the latest evidence on the effect of eliminating senescent endothelial cells (senolysis) and identify important remaining questions to be addressed in future studies.

Key points

  • Forming the inner lining of blood vessels, endothelial cells are exposed to a unique milieu of damaging stimuli, including haemodynamic forces as well as circulating and endothelium-derived factors.

  • Exposure to damaging stimuli results in telomeric and non-telomeric DNA damage, mitochondrial dysfunction and alterations in energy sensor pathways in endothelial cells.

  • Changes induced by damaging stimuli lead to the activation of tumour suppressor pathways, such as p53–p21 and pRb–p16, resulting in proliferative arrest and senescence.

  • Senescent endothelial cells are enlarged, flat and refractory to changes in response to shear stress; they are also metabolically active and secrete a variety of inflammatory molecules.

  • Senescent endothelial cells and their secreted factors are major contributors to arterial dysfunction and the pathophysiology of various cardiometabolic diseases.

  • Emerging evidence suggests that targeting senescent endothelial cells can be an effective strategy to suppress cardiometabolic diseases.

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Fig. 1: Morphological changes in senescent endothelial cells.
Fig. 2: Exposure of endothelial cells to circulating and endogenous stimuli.
Fig. 3: Mechanisms of endothelial cell senescence induced by damaging stimuli.
Fig. 4: Pathological consequences of endothelial cell senescence.

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Acknowledgements

The authors are supported by funding from National Institute of Health Awards R01 AG060395 (A.J.D.), R01 AG050238 (A.J.D.), R01 AG048366 (L.A.L.), F31AG076312 (S.I.B.) and Veteran’s Affairs Merit Review Award I01 BX004492 (L.A.L.) from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service. The contents of the Review do not represent the views of the United States Department of Veterans Affairs, the National Institutes of Health or the United States Government.

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  1. These authors contributed equally: Samuel I. Bloom, Md Torikul Islam.

Authors and Affiliations

  1. Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA

    Samuel I. Bloom, Md Torikul Islam, Lisa A. Lesniewski & Anthony J. Donato

  2. Department of Internal Medicine, Division of Geriatrics, University of Utah, Salt Lake City, UT, USA

    Lisa A. Lesniewski & Anthony J. Donato

  3. Veterans Affairs Medical Center–Salt Lake City, Geriatric Research Education and Clinical Center, Salt Lake City, UT, USA

    Lisa A. Lesniewski & Anthony J. Donato

  4. Department of Biochemistry, University of Utah, Salt Lake City, UT, USA

    Anthony J. Donato

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S.I.B. and M.T.I. researched data for the article. All the authors contributed substantially to discussion of the content, wrote the article, and reviewed and edited the manuscript before submission.

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A.J.D. is a scientific adviser and stockholder and L.A.L. is a stockholder in Recursion Pharmaceuticals. None of the work done with Recursion is outlined or discussed in this Review. The other authors declare no competing interests.

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Bloom, S.I., Islam, M.T., Lesniewski, L.A. et al. Mechanisms and consequences of endothelial cell senescence. Nat Rev Cardiol 20, 38–51 (2023). https://doi.org/10.1038/s41569-022-00739-0

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