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<p>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&#xa0;kDa and 3&#xa0;kDa) but exhibited increased permeability to small tracers (0.3&#xa0;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.</p>

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Long-term cerebrovascular effects of cyclophosphamide and vincristine: endothelial senescence, impaired DNA repair signaling, and blood–brain barrier dysfunction

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月30日

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  • 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

摘要

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.