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Mechanisms and consequences of endothelial cell senescence

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.

References

  1. Campisi, J. & d’Adda di Fagagna, F. Cellular senescence: when bad things happen to good cells. Nat. Rev. Mol. Cell Biol. 8, 729–740 (2007).

    CAS  PubMed  Article  Google Scholar 

  2. Yousefzadeh, M. J. et al. Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice. Aging Cell 19, e13094 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. Grosse, L. et al. Defined p16(High) senescent cell types are indispensable for mouse healthspan. Cell Metab. 32, 87–99.e6 (2020).

    CAS  PubMed  Article  Google Scholar 

  4. Cohen, C. et al. Glomerular endothelial cell senescence drives age-related kidney disease through PAI-1. EMBO Mol. Med. 13, e14146 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. Shosha, E. et al. Mechanisms of diabetes-induced endothelial cell senescence: role of arginase 1. Int. J. Mol. Sci. 19, 1215 (2018).

    PubMed Central  Article  CAS  Google Scholar 

  6. Kiss, T. et al. Single-cell RNA sequencing identifies senescent cerebromicrovascular endothelial cells in the aged mouse brain. Geroscience 42, 429–444 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  7. Yokoi, T. et al. Apoptosis signal-regulating kinase 1 mediates cellular senescence induced by high glucose in endothelial cells. Diabetes 55, 1660–1665 (2006).

    CAS  PubMed  Article  Google Scholar 

  8. Hayashi, T. et al. Endothelial cellular senescence is inhibited by liver X receptor activation with an additional mechanism for its atheroprotection in diabetes. Proc. Natl Acad. Sci. USA 111, 1168–1173 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. Gasek, N. S., Kuchel, G. A., Kirkland, J. L. & Xu, M. Strategies for targeting senescent cells in human disease. Nat. Aging 1, 870–879 (2021).

    PubMed  PubMed Central  Article  Google Scholar 

  10. Dolgin, E. Send in the senolytics. Nat. Biotechnol. 38, 1371–1377 (2020).

    CAS  PubMed  Article  Google Scholar 

  11. Jurk, D. & Passos, J. F. Senolytic drugs: beyond the promise and the hype. Mech. Ageing Dev. 202, 111631 (2022).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. Zhu, Y. et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644–658 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. Zhu, Y. et al. New agents that target senescent cells: the flavone, fisetin, and the BCL-X(L) inhibitors, A1331852 and A1155463. Aging 9, 955–963 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  14. Palmer, A. K., Tchkonia, T. & Kirkland, J. L. Senolytics: potential for alleviating diabetes and its complications. Endocrinology 162, bqab058 (2021).

    PubMed  PubMed Central  Article  Google Scholar 

  15. Raffaele, M. & Vinciguerra, M. The costs and benefits of senotherapeutics for human health. Lancet Healthy Longev. 3, e67–e77 (2022).

    Article  Google Scholar 

  16. Wissler Gerdes, E. O., Misra, A., Netto, J. M. E., Tchkonia, T. & Kirkland, J. L. Strategies for late phase preclinical and early clinical trials of senolytics. Mech. Ageing Dev. 200, 111591 (2021).

    CAS  PubMed  Article  Google Scholar 

  17. Donato, A. J., Morgan, R. G., Walker, A. E. & Lesniewski, L. A. Cellular and molecular biology of aging endothelial cells. J. Mol. Cell Cardiol. 89, 122–135 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. De Cecco, M. et al. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 566, 73–78 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  19. Uryga, A. K. et al. Telomere damage promotes vascular smooth muscle cell senescence and immune cell recruitment after vessel injury. Commun. Biol. 4, 611 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Wang, B. et al. An inducible p21-Cre mouse model to monitor and manipulate p21-highly-expressing senescent cells in vivo. Nat. Aging 1, 962–973 (2021).

    PubMed  PubMed Central  Article  Google Scholar 

  21. Wang, L. et al. Targeting p21(Cip1) highly expressing cells in adipose tissue alleviates insulin resistance in obesity. Cell Metab. 34, 75–89.e8 (2022).

    CAS  PubMed  Article  Google Scholar 

  22. d’Adda di Fagagna, F. Living on a break: cellular senescence as a DNA-damage response. Nat. Rev. Cancer 8, 512–522 (2008).

    PubMed  Article  CAS  Google Scholar 

  23. Childs, B. G., Baker, D. J., Kirkland, J. L., Campisi, J. & van Deursen, J. M. Senescence and apoptosis: dueling or complementary cell fates? EMBO Rep. 15, 1139–1153 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. Hsu, C. H., Altschuler, S. J. & Wu, L. F. Patterns of early p21 dynamics determine proliferation-senescence cell fate after chemotherapy. Cell 178, 361–373.e12 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. Lee, B. Y. et al. Senescence-associated β-galactosidase is lysosomal β-galactosidase. Aging Cell 5, 187–195 (2006).

    CAS  PubMed  Article  Google Scholar 

  26. Kohli, J. et al. Algorithmic assessment of cellular senescence in experimental and clinical specimens. Nat. Protoc. 16, 2471–2498 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. González-Gualda, E., Baker, A. G., Fruk, L. & Muñoz-Espín, D. A guide to assessing cellular senescence in vitro and in vivo. FEBS J. 288, 56–80 (2021).

    PubMed  Article  CAS  Google Scholar 

  28. Wiley, C. D. et al. Analysis of individual cells identifies cell-to-cell variability following induction of cellular senescence. Aging Cell 16, 1043–1050 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Hernandez-Segura, A. et al. Unmasking transcriptional heterogeneity in senescent cells. Curr. Biol. 27, 2652–2660.e4 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. Basisty, N. et al. A proteomic atlas of senescence-associated secretomes for aging biomarker development. PLoS Biol. 18, e3000599 (2020).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  31. Coppé, J. P., Desprez, P. Y., Krtolica, A. & Campisi, J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu. Rev. Pathol. 5, 99–11 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  32. Chala, N. et al. Mechanical fingerprint of senescence in endothelial cells. Nano Lett. 21, 4911–4920 (2021).

    CAS  PubMed  Article  Google Scholar 

  33. Wang, C., Baker, B. M., Chen, C. S. & Schwartz, M. A. Endothelial cell sensing of flow direction. Arterioscler. Thromb. Vasc. Biol. 33, 2130–2136 (2013).

    CAS  PubMed  Article  Google Scholar 

  34. Lafargue, A. et al. Ionizing radiation induces long-term senescence in endothelial cells through mitochondrial respiratory complex II dysfunction and superoxide generation. Free Radic. Biol. Med. 108, 750–759 (2017).

    CAS  PubMed  Article  Google Scholar 

  35. Huo, J. et al. Coenzyme Q10 prevents senescence and dysfunction caused by oxidative stress in vascular endothelial cells. Oxid. Med. Cell Longev. 2018, 3181759 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  36. Donato, A. J. et al. Direct evidence of endothelial oxidative stress with aging in humans: relation to impaired endothelium-dependent dilation and upregulation of nuclear factor-κB. Circ. Res. 100, 1659–1666 (2007).

    CAS  PubMed  Article  Google Scholar 

  37. Khan, S. Y. et al. Premature senescence of endothelial cells upon chronic exposure to TNFα can be prevented by N-acetyl cysteine and plumericin. Sci. Rep. 7, 39501 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. Yin, Y. et al. Vascular endothelial cells senescence is associated with NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation via reactive oxygen species (ROS)/thioredoxin-interacting protein (TXNIP) pathway. Int. J. Biochem. Cell Biol. 84, 22–34 (2017).

    CAS  PubMed  Article  Google Scholar 

  39. Bent, E. H., Gilbert, L. A. & Hemann, M. T. A senescence secretory switch mediated by PI3K/AKT/mTOR activation controls chemoprotective endothelial secretory responses. Genes Dev. 30, 1811–1821 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. Hampel, B. et al. Increased expression of extracellular proteins as a hallmark of human endothelial cell in vitro senescence. Exp. Gerontol. 41, 474–481 (2006).

    CAS  PubMed  Article  Google Scholar 

  41. Hwang, H. J. et al. Endothelial cells under therapy-induced senescence secrete CXCL11, which increases aggressiveness of breast cancer cells. Cancer Lett. 490, 100–110 (2020).

    CAS  PubMed  Article  Google Scholar 

  42. Ghosh, A. K. et al. A small molecule inhibitor of PAI-1 protects against doxorubicin-induced cellular senescence. Oncotarget 7, 72443–72457 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  43. Grillari, J., Hohenwarter, O., Grabherr, R. M. & Katinger, H. Subtractive hybridization of mRNA from early passage and senescent endothelial cells. Exp. Gerontol. 35, 187–197 (2000).

    CAS  PubMed  Article  Google Scholar 

  44. Chen, L., Holder, R., Porter, C. & Shah, Z. Vitamin D3 attenuates doxorubicin-induced senescence of human aortic endothelial cells by upregulation of IL-10 via the pAMPKα/Sirt1/Foxo3a signaling pathway. PLoS ONE 16, e0252816 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. Li, R. et al. Long-term stimulation of angiotensin II induced endothelial senescence and dysfunction. Exp. Gerontol. 119, 212–220 (2019).

    CAS  PubMed  Article  Google Scholar 

  46. Shelton, D. N., Chang, E., Whittier, P. S., Choi, D. & Funk, W. D. Microarray analysis of replicative senescence. Curr. Biol. 9, 939–945 (1999).

    CAS  PubMed  Article  Google Scholar 

  47. Lee, O. H. et al. Sirtuin 6 deficiency induces endothelial cell senescence via downregulation of forkhead box M1 expression. Aging 12, 20946–20967 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. Minamino, T. et al. Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation 105, 1541–1544 (2002).

    CAS  PubMed  Article  Google Scholar 

  49. Coleman, P. R. et al. Stress-induced premature senescence mediated by a novel gene, SENEX, results in an anti-inflammatory phenotype in endothelial cells. Blood 116, 4016–4024 (2010).

    CAS  PubMed  Article  Google Scholar 

  50. Coleman, P. R. et al. Age-associated stresses induce an anti-inflammatory senescent phenotype in endothelial cells. Aging 5, 913–924 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. Powter, E. E. et al. Caveolae control the anti-inflammatory phenotype of senescent endothelial cells. Aging Cell 14, 102–111 (2015).

    CAS  PubMed  Article  Google Scholar 

  52. Kamino, H. et al. Searching for genes involved in arteriosclerosis: proteomic analysis of cultured human umbilical vein endothelial cells undergoing replicative senescence. Cell Struct. Funct. 28, 495–503 (2003).

    CAS  PubMed  Article  Google Scholar 

  53. Bautista-Niño, P. K. et al. Local endothelial DNA repair deficiency causes aging-resembling endothelial-specific dysfunction. Clin. Sci. 134, 727–746 (2020).

    Article  Google Scholar 

  54. Barinda, A. J. et al. Endothelial progeria induces adipose tissue senescence and impairs insulin sensitivity through senescence associated secretory phenotype. Nat. Commun. 11, 481 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. Nelson, G. et al. A senescent cell bystander effect: senescence-induced senescence. Aging Cell 11, 345–349 (2012).

    CAS  PubMed  Article  Google Scholar 

  56. Erusalimsky, J. D. Vascular endothelial senescence: from mechanisms to pathophysiology. J. Appl. Physiol. 106, 326–332 (2009).

    CAS  PubMed  Article  Google Scholar 

  57. Woywodt, A., Bahlmann, F. H., De Groot, K., Haller, H. & Haubitz, M. Circulating endothelial cells: life, death, detachment and repair of the endothelial cell layer. Nephrol. Dial. Transpl. 17, 1728–1730 (2002).

    Article  Google Scholar 

  58. Hobson, B. & Denekamp, J. Endothelial proliferation in tumours and normal tissues: continuous labelling studies. Br. J. Cancer 49, 405–413 (1984).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. Chiu, J. J. & Chien, S. Effects of disturbed flow on vascular endothelium: pathophysiological basis and clinical perspectives. Physiol. Rev. 91, 327–387 (2011).

    PubMed  Article  Google Scholar 

  60. Kotla, S. et al. Endothelial senescence is induced by phosphorylation and nuclear export of telomeric repeat binding factor 2-interacting protein. JCI Insight 4, e124867 (2019).

    PubMed Central  Article  Google Scholar 

  61. Warboys, C. M. et al. Disturbed flow promotes endothelial senescence via a p53-dependent pathway. Arterioscler. Thromb. Vasc. Biol. 34, 985–995 (2014).

    CAS  PubMed  Article  Google Scholar 

  62. Chang, E. & Harley, C. B. Telomere length and replicative aging in human vascular tissues. Proc. Natl Acad. Sci. USA 92, 11190–11194 (1995).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. Vaupel, P., Kallinowski, F. & Okunieff, P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res. 49, 6449–6465 (1989).

    CAS  PubMed  Google Scholar 

  64. Richardson, R. S. et al. Human skeletal muscle intracellular oxygenation: the impact of ambient oxygen availability. J. Physiol. 571, 415–424 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. Chen, Q., Fischer, A., Reagan, J. D., Yan, L. J. & Ames, B. N. Oxidative DNA damage and senescence of human diploid fibroblast cells. Proc. Natl Acad. Sci. USA 92, 4337–4341 (1995).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. von Zglinicki, T., Saretzki, G., Döcke, W. & Lotze, C. Mild hyperoxia shortens telomeres and inhibits proliferation of fibroblasts: a model for senescence? Exp. Cell Res. 220, 186–193 (1995).

    Article  Google Scholar 

  67. Parrinello, S. et al. Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nat. Cell Biol. 5, 741–747 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. Lee, A. C. et al. Ras proteins induce senescence by altering the intracellular levels of reactive oxygen species. J. Biol. Chem. 274, 7936–7940 (1999).

    CAS  PubMed  Article  Google Scholar 

  69. Packer, L. & Fuehr, K. Low oxygen concentration extends the lifespan of cultured human diploid cells. Nature 267, 423–425 (1977).

    CAS  PubMed  Article  Google Scholar 

  70. Busuttil, R. A., Rubio, M., Dollé, M. E., Campisi, J. & Vijg, J. Oxygen accelerates the accumulation of mutations during the senescence and immortalization of murine cells in culture. Aging Cell 2, 287–294 (2003).

    CAS  PubMed  Article  Google Scholar 

  71. Basu, R. et al. Effects of age and sex on postprandial glucose metabolism: differences in glucose turnover, insulin secretion, insulin action, and hepatic insulin extraction. Diabetes 55, 2001–2014 (2006).

    CAS  PubMed  Article  Google Scholar 

  72. Issa, J. S., Diament, J. & Forti, N. Postprandial lipemia: influence of aging. Arq. Bras. Cardiol. 85, 15–19 (2005).

    PubMed  Article  Google Scholar 

  73. Lindberg, O., Tilvis, R. S. & Strandberg, T. E. Does fasting plasma insulin increase by age in the general elderly population? Aging 9, 277–280 (1997).

    CAS  PubMed  Google Scholar 

  74. Trott, D. W. et al. T lymphocyte depletion ameliorates age-related metabolic impairments in mice. Geroscience 43, 1331–1347 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. Prattichizzo, F. et al. Short-term sustained hyperglycaemia fosters an archetypal senescence-associated secretory phenotype in endothelial cells and macrophages. Redox Biol. 15, 170–181 (2018).

    CAS  PubMed  Article  Google Scholar 

  76. Zhong, W., Zou, G., Gu, J. & Zhang, J. L-arginine attenuates high glucose-accelerated senescence in human umbilical vein endothelial cells. Diabetes Res. Clin. Pract. 89, 38–45 (2010).

    CAS  PubMed  Article  Google Scholar 

  77. Hayashi, T. et al. Endothelial cellular senescence is inhibited by nitric oxide: implications in atherosclerosis associated with menopause and diabetes. Proc. Natl Acad. Sci. USA 103, 17018–17023 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. Maeda, M., Hayashi, T., Mizuno, N., Hattori, Y. & Kuzuya, M. Intermittent high glucose implements stress-induced senescence in human vascular endothelial cells: role of superoxide production by NADPH oxidase. PLoS ONE 10, e0123169 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  79. Mortuza, R., Chen, S., Feng, B., Sen, S. & Chakrabarti, S. High glucose induced alteration of SIRTs in endothelial cells causes rapid aging in a p300 and FOXO regulated pathway. PLoS ONE 8, e54514 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. Liu, J. et al. Glucose-induced oxidative stress and accelerated aging in endothelial cells are mediated by the depletion of mitochondrial SIRTs. Physiol. Rep. 8, e14331 (2020).

    PubMed  PubMed Central  Google Scholar 

  81. Brodsky, S. V. et al. Prevention and reversal of premature endothelial cell senescence and vasculopathy in obesity-induced diabetes by ebselen. Circ. Res. 94, 377–384 (2004).

    CAS  PubMed  Article  Google Scholar 

  82. Yokoyama, M. et al. Inhibition of endothelial p53 improves metabolic abnormalities related to dietary obesity. Cell Rep. 7, 1691–1703 (2014).

    CAS  PubMed  Article  Google Scholar 

  83. Miyauchi, H. et al. Akt negatively regulates the in vitro lifespan of human endothelial cells via a p53/p21-dependent pathway. EMBO J. 23, 212–220 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. Hayashi, T. et al. Nitric oxide and endothelial cellular senescence. Pharmacol. Ther. 120, 333–339 (2008).

    CAS  PubMed  Article  Google Scholar 

  85. Oh, S. T., Park, H., Yoon, H. J. & Yang, S. Y. Long-term treatment of native LDL induces senescence of cultured human endothelial cells. Oxid. Med. Cell Longev. 2017, 6487825 (2017).

    PubMed  PubMed Central  Google Scholar 

  86. Jiang, Y. H., Jiang, L. Y., Wang, Y. C., Ma, D. F. & Li, X. Quercetin attenuates atherosclerosis via modulating oxidized LDL-induced endothelial cellular senescence. Front. Pharmacol. 11, 512 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. Liu, R., Cheng, F., Zeng, K., Li, W. & Lan, J. GPR120 agonist GW9508 ameliorated cellular senescence induced by ox-LDL. ACS Omega 5, 32195–32202 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. Zhang, D. et al. Homocysteine accelerates senescence of endothelial cells via DNA hypomethylation of human telomerase reverse transcriptase. Arterioscler. Thromb. Vasc. Biol. 35, 71–78 (2015).

    PubMed  Article  CAS  Google Scholar 

  89. Shi, Q. et al. Endothelial senescence after high-cholesterol, high-fat diet challenge in baboons. Am. J. Physiol. Heart Circ. Physiol. 292, H2913–H2920 (2007).

    CAS  PubMed  Article  Google Scholar 

  90. Albertini, E., Kozieł, R., Dürr, A., Neuhaus, M. & Jansen-Dürr, P. Cystathionine beta synthase modulates senescence of human endothelial cells. Aging 4, 664–673 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. Scalera, F. et al. Effect of L-arginine on asymmetric dimethylarginine (ADMA) or homocysteine-accelerated endothelial cell aging. Biochem. Biophys. Res. Commun. 345, 1075–1082 (2006).

    CAS  PubMed  Article  Google Scholar 

  92. Xu, D., Neville, R. & Finkel, T. Homocysteine accelerates endothelial cell senescence. FEBS Lett. 470, 20–24 (2000).

    CAS  PubMed  Article  Google Scholar 

  93. Xing, S. S. et al. Salidroside attenuates endothelial cellular senescence via decreasing the expression of inflammatory cytokines and increasing the expression of SIRT3. Mech. Ageing Dev. 175, 1–6 (2018).

    CAS  PubMed  Article  Google Scholar 

  94. Parkhitko, A. A., Jouandin, P., Mohr, S. E. & Perrimon, N. Methionine metabolism and methyltransferases in the regulation of aging and lifespan extension across species. Aging Cell 18, e13034 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. Gimbrone, M. A. Jr & García-Cardeña, G. Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circ. Res. 118, 620–636 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. Yamazaki, Y. et al. Vascular cell senescence contributes to blood-brain barrier breakdown. Stroke 47, 1068–1077 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  97. Krouwer, V. J., Hekking, L. H., Langelaar-Makkinje, M., Regan-Klapisz, E. & Post, J. A. Endothelial cell senescence is associated with disrupted cell-cell junctions and increased monolayer permeability. Vasc. Cell 4, 12 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. Oeseburg, H. et al. Bradykinin protects against oxidative stress-induced endothelial cell senescence. Hypertension 53, 417–422 (2009).

    CAS  PubMed  Article  Google Scholar 

  99. Vasa, M., Breitschopf, K., Zeiher, A. M. & Dimmeler, S. Nitric oxide activates telomerase and delays endothelial cell senescence. Circ. Res. 87, 540–542 (2000).

    CAS  PubMed  Article  Google Scholar 

  100. Matsushita, H. et al. eNOS activity is reduced in senescent human endothelial cells: preservation by hTERT immortalization. Circ. Res. 89, 793–798 (2001).

    CAS  PubMed  Article  Google Scholar 

  101. Olmos, G. et al. Hyperphosphatemia induces senescence in human endothelial cells by increasing endothelin-1 production. Aging Cell 16, 1300–1312 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. Donato, A. J. et al. Vascular endothelial dysfunction with aging: endothelin-1 and endothelial nitric oxide synthase. Am. J. Physiol. Heart Circ. Physiol. 297, H425–H432 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. Shan, H., Bai, X. & Chen, X. Angiotensin II induces endothelial cell senescence via the activation of mitogen-activated protein kinases. Cell Biochem. Funct. 26, 459–466 (2008).

    CAS  PubMed  Article  Google Scholar 

  104. Khan, I. et al. Low dose chronic angiotensin ii induces selective senescence of kidney endothelial cells. Front. Cell Dev. Biol. 9, 782841 (2021).

    PubMed  PubMed Central  Article  Google Scholar 

  105. Kim, M. Y. et al. The PPARδ-mediated inhibition of angiotensin II-induced premature senescence in human endothelial cells is SIRT1-dependent. Biochem. Pharmacol. 84, 1627–1634 (2012).

    CAS  PubMed  Article  Google Scholar 

  106. Kandhaya-Pillai, R. et al. TNFα-senescence initiates a STAT-dependent positive feedback loop, leading to a sustained interferon signature, DNA damage, and cytokine secretion. Aging 9, 2411–2435 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. Yamagata, K., Suzuki, S. & Tagami, M. Docosahexaenoic acid prevented tumor necrosis factor alpha-induced endothelial dysfunction and senescence. Prostaglandins Leukot. Essent. Fatty Acids 104, 11–18 (2016).

    CAS  PubMed  Article  Google Scholar 

  108. Luu, A. Z. et al. Role of endothelium in doxorubicin-induced cardiomyopathy. JACC Basic Transl Sci. 3, 861–870 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  109. Terwoord, J. D., Beyer, A. M. & Gutterman, D. D. Endothelial dysfunction as a complication of anti-cancer therapy. Pharmacol. Ther. 237, 108116 (2022).

    CAS  PubMed  Article  Google Scholar 

  110. Yeh, E. T. et al. Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management. Circulation 109, 3122–3131 (2004).

    PubMed  Article  Google Scholar 

  111. Mongiardi, M. P. et al. Axitinib exposure triggers endothelial cells senescence through ROS accumulation and ATM activation. Oncogene 38, 5413–5424 (2019).

    CAS  PubMed  Article  Google Scholar 

  112. Clayton, Z. S. et al. Doxorubicin-induced oxidative stress and endothelial dysfunction in conduit arteries is prevented by mitochondrial-specific antioxidant treatment. JACC CardioOncol 2, 475–488 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  113. Clayton, Z. S. et al. Tumor necrosis factor alpha-mediated inflammation and remodeling of the extracellular matrix underlies aortic stiffening induced by the common chemotherapeutic agent doxorubicin. Hypertension 77, 1581–1590 (2021).

    CAS  PubMed  Article  Google Scholar 

  114. Hutton, D. et al. Cellular senescence mediates doxorubicin-induced arterial dysfunction via activation of mitochondrial oxidative stress and the mammalian target of rapamycin [abstract]. FASEB J. https://doi.org/10.1096/fasebj.2021.35.S1.00283 (2021).

  115. Merolle, M., Mongiardi, M. P., Piras, M., Levi, A. & Falchetti, M. L. Glioblastoma cells do not affect axitinib-dependent senescence of HUVECs in a transwell coculture model. Int. J. Mol. Sci. 21, 1490 (2020).

    CAS  PubMed Central  Article  Google Scholar 

  116. Wang, Y., Boerma, M. & Zhou, D. Ionizing radiation-induced endothelial cell senescence and cardiovascular diseases. Radiat. Res. 186, 153–161 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT04733534 (2022).

  118. McDonald, A. I. et al. Endothelial regeneration of large vessels is a biphasic process driven by local cells with distinct proliferative capacities. Cell Stem Cell 23, 210–225.e6 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. Hastings, R., Qureshi, M., Verma, R., Lacy, P. S. & Williams, B. Telomere attrition and accumulation of senescent cells in cultured human endothelial cells. Cell Prolif. 37, 317–324 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. Roake, C. M. & Artandi, S. E. Control of cellular aging, tissue function, and cancer by p53 downstream of telomeres. Cold Spring Harb. Perspect. Med. 7, a026088 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  121. Kurz, D. J. et al. Chronic oxidative stress compromises telomere integrity and accelerates the onset of senescence in human endothelial cells. J. Cell Sci. 117, 2417–2426 (2004).

    CAS  PubMed  Article  Google Scholar 

  122. von Zglinicki, T. Oxidative stress shortens telomeres. Trends Biochem. Sci. 27, 339–344 (2002).

    Article  Google Scholar 

  123. Hewitt, G. et al. Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nat. Commun. 3, 708 (2012).

    PubMed  Article  CAS  Google Scholar 

  124. Oikawa, S., Tada-Oikawa, S. & Kawanishi, S. Site-specific DNA damage at the GGG sequence by UVA involves acceleration of telomere shortening. Biochemistry 40, 4763–4768 (2001).

    CAS  PubMed  Article  Google Scholar 

  125. Anderson, R. et al. Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. EMBO J. 38, e100492 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  126. Morgan, R. G., Donato, A. J. & Walker, A. E. Telomere uncapping and vascular aging. Am. J. Physiol. Heart Circ. Physiol. 315, H1–H5 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. Morgan, R. G. et al. Age-related telomere uncapping is associated with cellular senescence and inflammation independent of telomere shortening in human arteries. Am. J. Physiol. Heart Circ. Physiol. 305, H251–H258 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. Morgan, R. G. et al. Role of arterial telomere dysfunction in hypertension: relative contributions of telomere shortening and telomere uncapping. J. Hypertens. 32, 1293–1299 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. Morgan, R. G. et al. Induced Trf2 deletion leads to aging vascular phenotype in mice associated with arterial telomere uncapping, senescence signaling, and oxidative stress. J. Mol. Cell Cardiol. 127, 74–82 (2019).

    CAS  PubMed  Article  Google Scholar 

  130. Bhayadia, R., Schmidt, B. M., Melk, A. & Hömme, M. Senescence-induced oxidative stress causes endothelial dysfunction. J. Gerontol. A Biol. Sci. Med. Sci. 71, 161–169 (2016).

    CAS  PubMed  Article  Google Scholar 

  131. Dominic, A., Banerjee, P., Hamilton, D. J., Le, N. T. & Abe, J. I. Time-dependent replicative senescence vs. disturbed flow-induced pre-mature aging in atherosclerosis. Redox Biol. 37, 101614 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. Liu, Y., Bloom, S. I. & Donato, A. J. The role of senescence, telomere dysfunction and shelterin in vascular aging. Microcirculation 26, e12487 (2019).

    PubMed  Article  Google Scholar 

  133. Zhan, H., Suzuki, T., Aizawa, K., Miyagawa, K. & Nagai, R. Ataxia telangiectasia mutated (ATM)-mediated DNA damage response in oxidative stress-induced vascular endothelial cell senescence. J. Biol. Chem. 285, 29662–29670 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. Kim, K. S., Kim, J. E., Choi, K. J., Bae, S. & Kim, D. H. Characterization of DNA damage-induced cellular senescence by ionizing radiation in endothelial cells. Int. J. Radiat. Biol. 90, 71–80 (2014).

    CAS  PubMed  Article  Google Scholar 

  135. Houtkooper, R. H., Pirinen, E. & Auwerx, J. Sirtuins as regulators of metabolism and healthspan. Nat. Rev. Mol. Cell Biol. 13, 225–238 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  136. Liu, R., Liu, H., Ha, Y., Tilton, R. G. & Zhang, W. Oxidative stress induces endothelial cell senescence via downregulation of Sirt6. Biomed. Res. Int. 2014, 902842 (2014).

    PubMed  PubMed Central  Google Scholar 

  137. Cardus, A., Uryga, A. K., Walters, G. & Erusalimsky, J. D. SIRT6 protects human endothelial cells from DNA damage, telomere dysfunction, and senescence. Cardiovasc. Res. 97, 571–579 (2013).

    CAS  PubMed  Article  Google Scholar 

  138. Zu, Y. et al. SIRT1 promotes proliferation and prevents senescence through targeting LKB1 in primary porcine aortic endothelial cells. Circ. Res. 106, 1384–1393 (2010).

    CAS  PubMed  Article  Google Scholar 

  139. Ota, H. et al. Sirt1 modulates premature senescence-like phenotype in human endothelial cells. J. Mol. Cell Cardiol. 43, 571–579 (2007).

    CAS  PubMed  Article  Google Scholar 

  140. Yuen, L. H. et al. A focused DNA-encoded chemical library for the discovery of inhibitors of NAD+-dependent enzymes. J. Am. Chem. Soc. 141, 5169–5181 (2019).

    CAS  PubMed  Article  Google Scholar 

  141. Chen, T. et al. SIRT3 protects endothelial cells from high glucose-induced senescence and dysfunction via the p53 pathway. Life Sci. 264, 118724 (2021).

    CAS  PubMed  Article  Google Scholar 

  142. Dikalova, A. E. et al. Mitochondrial deacetylase sirt3 reduces vascular dysfunction and hypertension while Sirt3 depletion in essential hypertension is linked to vascular inflammation and oxidative stress. Circ. Res. 126, 439–452 (2020).

    CAS  PubMed  Article  Google Scholar 

  143. Correia-Melo, C. & Passos, J. F. Mitochondria: are they causal players in cellular senescence? Biochim. Biophys. Acta 1847, 1373–1379 (2015).

    CAS  PubMed  Article  Google Scholar 

  144. Wiley, C. D. et al. Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell Metab. 23, 303–314 (2016).

    CAS  PubMed  Article  Google Scholar 

  145. Eelen, G. et al. Endothelial cell metabolism. Physiol. Rev. 98, 3–58 (2018).

    CAS  PubMed  Article  Google Scholar 

  146. Sakamuri, S. et al. Glycolytic and oxidative phosphorylation defects precede the development of senescence in primary human brain microvascular endothelial cells. Geroscience https://doi.org/10.1007/s11357-022-00550-2 (2022).

    Article  PubMed  Google Scholar 

  147. Voghel, G. et al. Chronic treatment with N-acetyl-cystein delays cellular senescence in endothelial cells isolated from a subgroup of atherosclerotic patients. Mech. Ageing Dev. 129, 261–270 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  148. Lener, B. et al. The NADPH oxidase Nox4 restricts the replicative lifespan of human endothelial cells. Biochem. J. 423, 363–374 (2009).

    CAS  PubMed  Article  Google Scholar 

  149. Donato, A. J., Machin, D. R. & Lesniewski, L. A. Mechanisms of dysfunction in the aging vasculature and role in age-related disease. Circ. Res. 123, 825–848 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  150. Csiszar, A., Wang, M., Lakatta, E. G. & Ungvari, Z. Inflammation and endothelial dysfunction during aging: role of NF-κB. J. Appl. Physiol. 105, 1333–1341 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  151. Rippe, C. et al. MicroRNA changes in human arterial endothelial cells with senescence: relation to apoptosis, eNOS and inflammation. Exp. Gerontol. 47, 45–51 (2012).

    CAS  PubMed  Article  Google Scholar 

  152. Tarantini, S. et al. Treatment with the BCL-2/BCL-xL inhibitor senolytic drug ABT263/navitoclax improves functional hyperemia in aged mice. Geroscience 43, 2427–2440 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  153. Roos, C. M. et al. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell 15, 973–977 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. Rossman, M. J. et al. Endothelial cell senescence with aging in healthy humans: prevention by habitual exercise and relation to vascular endothelial function. Am. J. Physiol. Heart Circ. Physiol. 313, H890–H895 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  155. Lähteenvuo, J. & Rosenzweig, A. Effects of aging on angiogenesis. Circ. Res. 110, 1252–1264 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  156. Islam, M. T. et al. Aging differentially impacts vasodilation and angiogenesis in arteries from the white and brown adipose tissues. Exp. Gerontol. 142, 111126 (2020).

    CAS  PubMed  Article  Google Scholar 

  157. El Maï, M. et al. The telomeric protein TRF2 regulates angiogenesis by binding and activating the PDGFRβ promoter. Cell Rep. 9, 1047–1060 (2014).

    PubMed  Article  CAS  Google Scholar 

  158. Franco, S., Segura, I., Riese, H. H. & Blasco, M. A. Decreased B16F10 melanoma growth and impaired vascularization in telomerase-deficient mice with critically short telomeres. Cancer Res. 62, 552–559 (2002).

    CAS  PubMed  Google Scholar 

  159. Zaccagnini, G. et al. Telomerase mediates vascular endothelial growth factor-dependent responsiveness in a rat model of hind limb ischemia. J. Biol. Chem. 280, 14790–14798 (2005).

    CAS  PubMed  Article  Google Scholar 

  160. Ungvari, Z. et al. Ionizing radiation promotes the acquisition of a senescence-associated secretory phenotype and impairs angiogenic capacity in cerebromicrovascular endothelial cells: role of increased DNA damage and decreased DNA repair capacity in microvascular radiosensitivity. J. Gerontol. A Biol. Sci. Med. Sci. 68, 1443–1457 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  161. Yoshida, Y. et al. p53-Induced inflammation exacerbates cardiac dysfunction during pressure overload. J. Mol. Cell Cardiol. 85, 183–198 (2015).

    CAS  PubMed  Article  Google Scholar 

  162. Chang, H. et al. Telomerase- and angiogenesis-related gene responses to irradiation in human umbilical vein endothelial cells. Int. J. Mol. Med. 31, 1202–1208 (2013).

    CAS  PubMed  Article  Google Scholar 

  163. Brühl, T. et al. p21Cip1 levels differentially regulate turnover of mature endothelial cells, endothelial progenitor cells, and in vivo neovascularization. Circ. Res. 94, 686–692 (2004).

    PubMed  Article  CAS  Google Scholar 

  164. Gogiraju, R. et al. Endothelial p53 deletion improves angiogenesis and prevents cardiac fibrosis and heart failure induced by pressure overload in mice. J. Am. Heart Assoc. 4, e001770 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  165. Gu, J. et al. Inhibition of p53 prevents diabetic cardiomyopathy by preventing early-stage apoptosis and cell senescence, reduced glycolysis, and impaired angiogenesis. Cell Death Dis. 9, 82 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  166. Akimoto, S., Mitsumata, M., Sasaguri, T. & Yoshida, Y. Laminar shear stress inhibits vascular endothelial cell proliferation by inducing cyclin-dependent kinase inhibitor p21(Sdi1/Cip1/Waf1). Circ. Res. 86, 185–190 (2000).

    CAS  PubMed  Article  Google Scholar 

  167. Crespo-Garcia, S. et al. Pathological angiogenesis in retinopathy engages cellular senescence and is amenable to therapeutic elimination via BCL-xL inhibition. Cell Metab. 33, 818–832.e7 (2021).

    CAS  PubMed  Article  Google Scholar 

  168. Claesson-Welsh, L., Dejana, E. & McDonald, D. M. Permeability of the endothelial barrier: identifying and reconciling controversies. Trends Mol. Med. 27, 314–331 (2021).

    CAS  PubMed  Article  Google Scholar 

  169. Salvador, E. et al. Senescence and associated blood-brain barrier alterations in vitro. Histochem. Cell Biol. 156, 283–292 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  170. Buford, T. W. Hypertension and aging. Ageing Res. Rev. 26, 96–111 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  171. Voghel, G. et al. Cellular senescence in endothelial cells from atherosclerotic patients is accelerated by oxidative stress associated with cardiovascular risk factors. Mech. Ageing Dev. 128, 662–671 (2007).

    CAS  PubMed  Article  Google Scholar 

  172. Westhoff, J. H. et al. Hypertension induces somatic cellular senescence in rats and humans by induction of cell cycle inhibitor p16INK4a. Hypertension 52, 123–129 (2008).

    CAS  PubMed  Article  Google Scholar 

  173. McCarthy, C. G., Wenceslau, C. F., Webb, R. C. & Joe, B. Novel contributors and mechanisms of cellular senescence in hypertension-associated premature vascular aging. Am. J. Hypertens. 32, 709–719 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  174. Pérez-Rivero, G. et al. Mice deficient in telomerase activity develop hypertension because of an excess of endothelin production. Circulation 114, 309–317 (2006).

    PubMed  Article  CAS  Google Scholar 

  175. de Montgolfier, O. et al. High systolic blood pressure induces cerebral microvascular endothelial dysfunction, neurovascular unit damage, and cognitive decline in mice. Hypertension 73, 217–228 (2019).

    PubMed  Article  CAS  Google Scholar 

  176. Islam, T. Impact of statins on vascular smooth muscle cells and relevance to atherosclerosis. J. Physiol. 598, 2295–2296 (2020).

    CAS  PubMed  Article  Google Scholar 

  177. Bentzon, J. F., Otsuka, F., Virmani, R. & Falk, E. Mechanisms of plaque formation and rupture. Circ. Res. 114, 1852–1866 (2014).

    CAS  PubMed  Article  Google Scholar 

  178. Childs, B. G. et al. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 354, 472–477 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  179. Honda, S. et al. Cellular senescence promotes endothelial activation through epigenetic alteration, and consequently accelerates atherosclerosis. Sci. Rep. 11, 14608 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  180. Yanaka, M. et al. Increased monocytic adhesion by senescence in human umbilical vein endothelial cells. Biosci. Biotechnol. Biochem. 75, 1098–1103 (2011).

    CAS  PubMed  Article  Google Scholar 

  181. Silva, G. C. et al. Replicative senescence promotes prothrombotic responses in endothelial cells: role of NADPH oxidase- and cyclooxygenase-derived oxidative stress. Exp. Gerontol. 93, 7–15 (2017).

    CAS  PubMed  Article  Google Scholar 

  182. Bochenek, M. L., Schütz, E. & Schäfer, K. Endothelial cell senescence and thrombosis: ageing clots. Thromb. Res. 147, 36–45 (2016).

    CAS  PubMed  Article  Google Scholar 

  183. Tsihlis, N. D. et al. Nitric oxide inhibits vascular smooth muscle cell proliferation and neointimal hyperplasia by increasing the ubiquitination and degradation of UbcH10. Cell Biochem. Biophys. 60, 89–97 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  184. Liu, Z. J. et al. Notch activation induces endothelial cell senescence and pro-inflammatory response: implication of Notch signaling in atherosclerosis. Atherosclerosis 225, 296–303 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  185. Zhu, Y. et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell 15, 428–435 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  186. Caland, L. et al. Knockdown of angiopoietin-like 2 induces clearance of vascular endothelial senescent cells by apoptosis, promotes endothelial repair and slows atherogenesis in mice. Aging 11, 3832–3850 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  187. Bai, B. et al. Cyclin-dependent kinase 5-mediated hyperphosphorylation of sirtuin-1 contributes to the development of endothelial senescence and atherosclerosis. Circulation 126, 729–740 (2012).

    CAS  PubMed  Article  Google Scholar 

  188. Dou, F. et al. PPARα targeting GDF11 inhibits vascular endothelial cell senescence in an atherosclerosis model. Oxid. Med. Cell Longev. 2021, 2045259 (2021).

    PubMed  PubMed Central  Google Scholar 

  189. Borlaug, B. A. & Redfield, M. M. Diastolic and systolic heart failure are distinct phenotypes within the heart failure spectrum. Circulation 123, 2006–2013 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  190. Paulus, W. J. & Tschöpe, C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J. Am. Coll. Cardiol. 62, 263–271 (2013).

    PubMed  Article  Google Scholar 

  191. Gevaert, A. B. et al. Endothelial senescence contributes to heart failure with preserved ejection fraction in an aging mouse model. Circ. Heart Fail. 10, e003806 (2017).

    CAS  PubMed  Article  Google Scholar 

  192. Shah, S. J. et al. Phenotype-specific treatment of heart failure with preserved ejection fraction: a multiorgan roadmap. Circulation 134, 73–90 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  193. Owens, W. A., Walaszczyk, A., Spyridopoulos, I., Dookun, E. & Richardson, G. D. Senescence and senolytics in cardiovascular disease: promise and potential pitfalls. Mech. Ageing Dev. 198, 111540 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  194. Riehle, C. & Bauersachs, J. Small animal models of heart failure. Cardiovasc. Res. 115, 1838–1849 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  195. Dookun, E. et al. Clearance of senescent cells during cardiac ischemia-reperfusion injury improves recovery. Aging Cell 19, e13249 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  196. Childs, B. G., Li, H. & van Deursen, J. M. Senescent cells: a therapeutic target for cardiovascular disease. J. Clin. Invest. 128, 1217–1228 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  197. Lawrie, A. & Francis, S. E. Frataxin and endothelial cell senescence in pulmonary hypertension. J. Clin. Invest. 131, e149721 (2021).

    CAS  PubMed Central  Article  Google Scholar 

  198. van der Feen, D. E. et al. Cellular senescence impairs the reversibility of pulmonary arterial hypertension. Sci. Transl Med. 12, eaaw4974 (2020).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  199. Culley, M. K. et al. Frataxin deficiency promotes endothelial senescence in pulmonary hypertension. J. Clin. Invest. 131, e136459 (2021).

    CAS  PubMed Central  Article  Google Scholar 

  200. Graupera, M. & Claret, M. Endothelial cells: new players in obesity and related metabolic disorders. Trends Endocrinol. Metab. 29, 781–794 (2018).

    CAS  PubMed  Article  Google Scholar 

  201. Hasegawa, Y. et al. Blockade of the nuclear factor-κB pathway in the endothelium prevents insulin resistance and prolongs life spans. Circulation 125, 1122–1133 (2012).

    CAS  PubMed  Article  Google Scholar 

  202. Garrido, A. M. et al. Efficacy and limitations of senolysis in atherosclerosis. Cardiovasc. Res. 118, 1713–1727 (2022).

    CAS  PubMed  Article  Google Scholar 

  203. Zhu, F. et al. Senescent cardiac fibroblast is critical for cardiac fibrosis after myocardial infarction. PLoS ONE 8, e74535 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  204. Meyer, K., Hodwin, B., Ramanujam, D., Engelhardt, S. & Sarikas, A. Essential role for premature senescence of myofibroblasts in myocardial fibrosis. J. Am. Coll. Cardiol. 67, 2018–2028 (2016).

    CAS  PubMed  Article  Google Scholar 

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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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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 (2022). https://doi.org/10.1038/s41569-022-00739-0

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