Abstract
Endothelial cells senescence is a physiological process affecting vascular integrity. It can contribute to heart and arterial stiffening and remodeling, impaired angiogenesis, defective vascular repair, and with an increasing prevalence of atherosclerosis. Drugs used as antineoplastic therapies, targeting tumor as well as endothelial cells, can also trigger endothelial cells senescence. We demonstrated that a short pulse of axitinib, a specific inhibitor of vascular endothelial growth factor receptors, induces cell senescence of endothelial cells. Here, we performed a high-throughput gene expression analysis to characterize the response of proliferating versus senescent endothelial cells to hypoxia, the main trigger of neo-angiogenetic phenomena in tumors. We compared the response to hypoxia of replicative senescent cells, with that of axitinib or of DNA damage-induced senescence. Overall, we enlightened common and specific responses to different senescence inducers and changes in the Senescent Associated Secretory Phenotype.
References
Erusalimsky JD (2009) Vascular endothelial senescence: from mechanisms to pathophysiology. J Appl Physiol 106:326–332
Kovacic JC, Moreno P, Nabel EG et al (2011) Cellular senescence, vascular disease, and aging. Circulation 123:1900–1910
Demaria M, O’Leary MN, Chang J et al (2017) Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discov 7:165–176
Mongiardi MP, Radice G, Piras M et al (2019) Axitinib exposure triggers endothelial cells senescence through ROS accumulation and ATM activation. Oncogene 1:1. https://doi.org/10.1038/s41388-019-0798-2
Bencokova Z, Kaufmann MR, Pires IM et al (2009) ATM activation and signaling under hypoxic conditions. Mol Cell Biol 29:526–537
Di Mitri D, Alimonti A (2016) Non-cell-autonomous regulation of cellular senescence in cancer. Trends Cell Biol 26:215–226
Coppé J-P, Patil CK, Rodier F et al (2008) Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 6:e301
Bolger AM, Lohse M, Usadel B (2014) Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30:2114–2120
Langmead B, Trapnell C, Salzberg S (2009) Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol 10:R25
Trapnell C, Pachter L, Salzberg SL (2009) TopHat: discovering splice junctions withRNA-Seq. Bioinformatics 25:1105–1111
Trapnell C, Roberts A, Goff L et al (2013) Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat Protoc 7:562–578
Acknowledgements
This work was supported by the National Research Council of Italy (CNR), Research Project “Aging: molecular and technological innovations for improving the health of the elderly population” (Prot. MIUR 2867 25.11.2011) to AL and MLF.
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All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Maria Patrizia Mongiardi, Matilde Merolle and Valentina Fustaino. The first draft of the manuscript was written by Maria Laura Falchetti and Andrea Levi. All authors read and approved the final manuscript.
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Mongiardi, M.P., Merolle, M., Fustaino, V. et al. Gene expression profiling of hypoxic response in different models of senescent endothelial cells. Aging Clin Exp Res 33, 1993–2001 (2021). https://doi.org/10.1007/s40520-019-01390-5
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DOI: https://doi.org/10.1007/s40520-019-01390-5