Cyclophosphamide and vincristine increased p16+ endothelial cells, downregulated DNA repair genes, and increased blood-brain barrier permeability 2 months post-treatment in mice.
Does cyclophosphamide or vincristine induce persistent endothelial senescence and blood-brain barrier dysfunction in young adult mice?
Cyclophosphamide and vincristine induce persistent cerebrovascular endothelial senescence, suppressed DNA-repair signaling, and chronic blood-brain barrier dysfunction in mice.
Cancer survivors frequently develop long-lasting cognitive impairment, yet the physiological mechanisms underlying these chronic effects remain poorly defined. We previously reported that methotrexate and cisplatin induce endothelial senescence in p16-3MR mice eventually leading to blood-brain barrier (BBB) impairments. Here, we investigated whether two widely used chemotherapy drugs, cyclophosphamide (CP) and vincristine (VIN), similarly induce persistent endothelial senescence and BBB dysfunction in young adult mice. We hypothesized that CP and VIN cause long-term cerebrovascular injury characterized by endothelial senescence, suppressed DNA damage-repair signaling, and chronic BBB leakage even months after treatment. Young (3-month-old) C57BL/6J mice received a clinically relevant CP or VIN treatment regimen, followed by a 2-month recovery period. Cerebrovascular endothelial senescence was assessed by p16+ immunofluorescence. Changes in the DNA damage/repair pathways were assessed using a TaqMan qPCR array. BBB permeability was measured in vivo using FITC-dextran with decreasing series of molecular weight (40, 3 and 0.3 kDa) using intravital two-photon imaging. CP markedly increased p16+ endothelial cells compared to controls, while VIN induced a moderate but significant elevation. qPCR analysis revealed broad downregulation of DNA damage-response and repair genes in both treatment groups, consistent with impaired proliferative capacity. BBB assessment demonstrated increased permeability to 0.3 kDa tracer in CP-treated mice, indicating sustained barrier impairment two months post-treatment. Our data indicates that cerebrovascular toxicity persists after CP and VIN exposure. Chemotherapy-induced endothelial senescence, suppressed DNA-repair signaling, and chronic BBB dysfunction may collectively contribute to chemotherapy-induced cerebrovascular pathophysiology. These findings extend our prior work using methotrexate and cisplatin and suggest that different chemotherapy agents -although to varying extents- ultimately converge on a common vascular-senescence pathway. Funding: RF1AG072295, R01AG055395, R01AG068295, R01AG070915, R01NS100782, R01CA255840, https://doi.org/10.58275/AHA.24CDA1276505.pc.gr.193648 , AHA CDA941290. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Kordestan et al. (Fri,) conducted a other in Chemotherapy-induced cerebrovascular injury. Cyclophosphamide and vincristine vs. Controls was evaluated on Cerebrovascular endothelial senescence, DNA damage/repair pathways, and blood-brain barrier permeability. Cyclophosphamide and vincristine increased p16+ endothelial cells, downregulated DNA repair genes, and increased blood-brain barrier permeability 2 months post-treatment in mice.