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Senescence inhibition by rapamycin mitigates radiation-induced atherosclerotic characteristics in human coronary endothelial cells

ABSTRACT: Ionising radiation (IR) is a recognised risk factor for cardiovascular disease (CVD), yet the mechanisms linking it to exposure remain incompletely understood. We show that IR drives a pro-atherogenic phenotype in human coronary artery endothelial cells (HCAECs) through the induction of cellular senescence, and that rapamycin attenuates these effects. IR triggered hallmark senescence features, including elevated SA-β-galactosidase activity, nuclear enlargement, and increased CDKN1A and p53 expression. Functionally, irradiated HCAECs displayed impaired barrier integrity and heightened monocyte adhesion. Transcriptomic and proteomic profiling revealed broad IR-induced alterations enriched in DNA damage response, cell-cycle arrest, senescence, proteostasis, and immune-related pathways. These findings establish a mechanistic link between radiation-induced endothelial senescence and early atherogenic-associated dysfunction, demonstrating that senescence is a driver of vascular injury. Importantly, identifying mTOR inhibition as a promising strategy to counteract radiation-associated endothelial dysfunction. This work positions senescence as a tractable therapeutic target in radiation-induced vascular injury.

ORGANISM(S): Homo sapiens

PROVIDER: GSE323983 | GEO | 2026/06/24

REPOSITORIES: GEO

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Project description:Background: Radiation therapy is the standard of care for central nervous system tumours. Despite the success of radiation therapy in reducing tumour mass, irradiation (IR)-induced vasculopathies and neuroinflammation contribute to late-delayed complications, neurodegeneration, andpremature ageing in long-term cancer survivors. Mesenchymal stromal cells (MSCs) are adult stem cells that facilitate tissue integrity, homeostasis, and repair. Here, we investigated the potential of the iPSC-derived MSC(iMSC) secretome in immunomodulation and vasculature repair in response to radiation injury utilizing human cell lines. Methods: We generated iPSC-derived iMSC lines and evaluated the potential of their conditioned media (iMSC CM) to treat IR-induced injuries in human monocytes (THP1) and brain vascular endothelial cells (hCMEC/D3). We further assessed factors in the iMSC secretome, their modulation, and the molecular pathways they elicit. Results: Increasing doses of IR disturbed endothelial tube and spheroid formation in hCMEC/D3. When IR-injured hCMEC/D3 (IR ≤ 5 Gy) were treated with iMSC CM, endothelial cell viability, adherence, spheroid compactness, and proangiogenic sprout formation were significantly ameliorated, and IR-induced ROS levels were reduced. iMSC CM augmented tube formation in cocultures of hCMEC/D3 and iMSCs. Consistently, iMSC CM facilitated angiogenesis in a zebrafish model in vivo. Furthermore, iMSC CM suppressed IR-induced NFκB activation, TNF-α release, and ROS production in THP1 cells. Additionally, iMSC CM diminished NF-kB activation in THP1 cells cocultured with irradiated hCMEC/D3, iMSCs, or HMC3 microglial lines. The cytokine array revealed that iMSC CM contains the proangiogenic and immunosuppressive factors MCP1/CCL2, IL6, IL8/CXCL8, ANG (Angiogenin), GROα/CXCL1, and RANTES/CCL5. Common promoter regulatory elements were enriched in TF-binding motifs such as androgen receptor (ANDR) and GATA2. hCMEC/D3 phosphokinome profiling revealed increased expression of pro-survival factors, the PI3K/AKT/mTOR modulator PRAS40 and β-catenin in response to CM. The transcriptome analysis revealed increased expression of GATA2 in iMSCs and the enrichment of pathways involved in RNA metabolism, translation, mitochondrial respiration, DNA damage repair, and neurodevelopment. Conclusions: The iMSC secretome is a comodulated composite of proangiogenic and immunosuppressive factors that has the potential to alleviate radiation-induced vascular endothelial cell damage and immune activation.

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Senescence inhibition by rapamycin mitigates radiation-induced atherosclerotic characteristics in human coronary endothelial cells

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