Venkatasubramanian, R.; Mahoney, S. A.; Hutton, D. A.; VanDongen, N. S.; Brunt, V. E.; Greenberg, N. T.; Longtine, A. G.; Brandt, L.; Beyer, A. M.; Melov, S.; Campisi, J.; Rossman, M. J.; Seals, D. R.; Clayton, Z. S.

Background: Mechanisms underlying Doxorubicin (Doxo) chemotherapy-induced vascular endothelial dysfunction are incompletely understood. Objectives: 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. Methods: 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 increased flow in human arterioles. Results: Lower peak EDD with Doxo (75% vs. control, 93%; P<0.05) was prevented with GCV (94%; P<0.05) and ABT263 (95%; 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% vs. Control, 94%; P<0.05) which was prevented with concomitant incubation of Doxo with ABT263 (82%; P<0.05 vs. Doxo alone; P=0.63 vs. Control). Conclusion: 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.