Vascular permeability and hyperpermeability in a murine adenocarcinoma after fractionated radiotherapy: an ultrastructural tracer study

Large radiation doses cause postradiation vascular hyperpermeability by dis rupting endothelia. The cumulative sequences of small doses (fractionated r adiotherapy) standard in clinical practice cause it too, but not by endothe lial disruption: the mechanisms are unknown. In this study, correlated fluo rescent and ultrastructural localisation of a tracer revealed the architect ure, fine structure and function of microvessels in mouse AT17 tumours, bef ore and after 42 Gy fractionated radiation. Before irradiation, tumour vasc ular permeability lay in the normophysiological range defined by the gut an d cerebral cortex. A double barrier regulated permeability: vesicular trans port through the endothelial wall required approximately 2 h and then the b asement membrane charge barrier trapped tracer for 2 h longer. Irradiation abolished the double barrier: tracer passed instantly through both endothel ial wall and underlying basement membrane, forming diffusion haloes around microvessels within 2-5 min. Structurally, irradiated tumour microvessels w ere lined by a continuous and vital endothelium with closed interendothelia l junctions; endothelial basement membranes were intact, though loosened. I rradiated endothelia exhibited extremely active membrane motility and intra cellular vesicle trafficking. Radiation treatment raised vascular permeabil ity by enhancing transendothelial transcytosis, and by altering the passive filter properties of the subendothelial basement membrane. This type of va scular hyperpermeability should be susceptible to pharmacological modulatio n.