Cellular senescence mediates doxorubicin chemotherapy-induced vascular endothelial dysfunction: translational evidence of prevention with senolytic treatment. Am J Physiol Heart Circ Physiol 2025 Dec 01;329(6):H1672-H1683
Date
10/27/2025Pubmed ID
41143747Pubmed Central ID
PMC12704655DOI
10.1152/ajpheart.00712.2025Scopus ID
2-s2.0-105024255414 (requires institutional sign-in at Scopus site) 3 CitationsAbstract
Mechanisms underlying doxorubicin (Doxo) chemotherapy-induced vascular endothelial dysfunction are incompletely understood. This study aimed to determine the role of cellular senescence in mediating Doxo-induced vascular endothelial dysfunction and the influence of senolytic therapy as a therapeutic strategy to mitigate endothelial dysfunction with Doxo. Endothelial function [carotid artery endothelium-dependent dilation (EDD) to increasing concentrations of acetylcholine] and associated mechanisms were assessed in young adult p16-3MR mice [which allow for genetic-based clearance of senescent cells with ganciclovir (GCV)] injected with Doxo and subsequently treated with GCV or ABT263 (senolytic). We also assessed the influence of Doxo and ABT263 ex vivo on EDD to increase flow in human arterioles. Lower peak EDD with Doxo (75 ± 3% vs. control, 93 ± 1%; P < 0.05) was prevented with GCV (94 ± 1%; P < 0.05) and ABT263 (95 ± 2%; P < 0.05) treatment, which was mediated by preserved nitric oxide bioavailability and prevention of excess mitochondrial oxidative stress. In human arterioles, ex vivo Doxo exposure impaired peak EDD (Doxo, 32 ± 10% vs. Control, 94 ± 2%; P < 0.05), which was prevented with concomitant incubation of Doxo with ABT263 (82 ± 7%; P < 0.05 vs. Doxo alone; P = 0.63 vs. Control). We provide translational evidence that cellular senescence contributes to Doxo-induced vascular endothelial dysfunction and that senolytics hold promise for preserving vascular endothelial function following Doxo exposure.NEW & NOTEWORTHY We demonstrate that cellular senescence contributes to doxorubicin-related vascular endothelial dysfunction and establishes efficacy for the use of senolytic therapy to improve vascular function following doxorubicin administration. Mechanistically, we found that cellular senescence reduced NO bioavailability and promoted excessive production of vascular mitochondrial superoxide-related oxidative stress, both of which were prevented with senolytic therapy. We translated these findings to humans and showed that ex vivo exposure to doxorubicin impaired arteriole endothelial function, which was prevented with senolytic exposure.
Author List
Venkatasubramanian R, Mahoney SA, Hutton DA, VanDongen NS, Brunt VE, Greenberg NT, Longtine AG, Brandt L, Beyer AM, Melov S, Rossman MJ, Seals DR, Clayton ZSAuthor
Andreas M. Beyer PhD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Aniline CompoundsAnimals
Antibiotics, Antineoplastic
Arterioles
Carotid Arteries
Cellular Senescence
Doxorubicin
Endothelium, Vascular
Female
Humans
Male
Mice
Nitric Oxide
Oxidative Stress
Sulfonamides
Vasodilation
