Fig. 2.

Proposed scheme for the contribution of neurovascular senescence and endothelial dysfunction to WBI-induced cognitive decline. γ-irradiation induced DNA damage and cellular senescence in cells of the neurovascular unit, including endothelial cells, perivascular microglia, and astrocytes. Endothelial senescence results in functional and structural impairment of the cerebral microcirculation, including endothelial dysfunction, impairment of neurovascular coupling responses, and microvascular rarefaction, all of which contribute to a significant decline in cerebral blood flow (CBF). γ-irradiation-induced neurovascular senescence disrupts the blood brain barrier, exacerbating neuroinflammation. Heightened inflammatory status of the neurovascular unit, due to endothelial senescence and the increased secretion of pro-inflammatory SASP factors from senescent microglia and astrocytes exacerbates cerebromicrovascular dysfunction and neuroinflammation. The resulting ischemic and inflammatory foci play a role in the pathogenesis of cognitive impairment. The model predicts that the aforementioned senescence-related structural and functional cerebromicrovascular alterations synergize to promote cognitive impairment in patients treated with WBI