Long-term cerebrovascular effects of cyclophosphamide and vincristine: endothelial senescence, impaired DNA repair signaling, and blood–brain barrier dysfunction
Year: 2026
Type: article
Abstract: Chemotherapy-related cognitive impairment is increasingly recognized as a long-term consequence of cancer treatment, yet the contribution of the cerebrovascular system remains poorly defined. In this study, we investigated the long-term effects of clinically relevant treatment regimens with cyclophosphamide (CP) and vincristine (VIN) on cerebrovascular cellular senescence, associated molecular signatures, and downstream functional outcomes, including disruption of blood-brain barrier (BBB) integrity in a mouse model. Our results showed that CP induces a persistent cerebrovascular endothelial phenotype characterized by increased cellular senescence, upregulation of mRNA expression of DNA damage checkpoint regulators, and concomitant downregulation of key DNA repair genes. BBB integrity was preserved after CP treatment for larger molecular tracers (40 kDa and 3 kDa) but exhibited increased permeability to small tracers (0.3 kDa), measured by in vivo two-photon microscopy, indicating a subtle yet persistent disruption of barrier function. In contrast, VIN elicited a markedly attenuated and heterogeneous transcriptional response and did not produce detectable BBB impairment, underscoring agent-specific cerebrovascular effects of chemotherapy. Collectively, these findings suggest that chemotherapy induces a persistent cerebrovascular injury phenotype with features resembling vascular aging and reduced vascular resilience, providing a potential mechanistic link between systemic cancer therapy and long-term adverse effects on brain health.
Source: GeroScience
Authors: Dorina Nagy, Kiana Vali Kordestan, Roland Patai, Rafal Gulej, Siva Sai Chandragiri, Raghavendra Y. Nagaraja, Santny Shanmugarama, Shoba Ekambaram, Evelyn Brunner, Rebeka Kristof, Mark Nagykaldi, Parikshat Sirpal, Andriy Yabluchanskiy, Karl E. Balsara, Rene Y. McNall, Zoltan Ungvari, Anna Csiszar
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $2,890
Funders: American Heart Association, University of Oklahoma, Oklahoma Center for the Advancement of Science and Technology, National Institutes of Health, University of Oklahoma Health Sciences Center, National Research, Development and Innovation Office, National Institute on Aging, National Cancer Institute, National Institute of Neurological Disorders and Stroke
Awards: Time restricted eating for prevention of age-related vascular cognitive decline in older adults, G1175738181, G1366693975, G1603123972, G1929630399, G2056304158, G2606335010, G2697612959, G2923601805, G2934755680, G3218036830, G4027441995, G4829972351, Radiation-induced astrocyte dysfunction and cognitive decline, Investigating the Impact of Accelerated Senescence on Cerebral Microhemorrhage Formation, Targeting Endothelial Senescence to Prevent Late-Onset Cerebrovascular Injury After Cancer Therapy, G6101597503, G6921692548, G70098445, G732383843
OpenAlex ID: W7159587590