Vascular function underlies enhanced intestinal regeneration after FLASH radiation [bulk RNAseq]

Using whole-abdominal irradiation, intestinal organoids, single-cell transcriptomics, spatial vascular phenotyping, and genetic, pharmacological, and physiological perturbations, we show that the intestinal FLASH effect is the result of active heterotypic vascular-epithelial crosstalk rather than passive radiochemical protection.

FLASH preserves endothelial tone and perfusion along the crypt–villus axis, averting phospho-MLC–dependent vascular collapse caused by conventional irradiation. This maintains the physiological oxygen gradient and licenses early, YAP-dependent regeneration that shields transit-amplifying secretory progenitors from persistent DNA damage and drives rapid crypt reconstitution. Disrupting the oxygen gradient directly, or indirectly through endothelial VEGFR2 blockade, abolishes FLASH sparing—reinstating progenitor DNA damage, loss of DCLK1⁺ and CHGA⁺ cells, and impaired regeneration.