Vascular permeability and hyperpermeability in a murine adenocarcinoma after fractionated radiotherapy: an ultrastructural tracer study.
Large radiation doses cause postradiation vascular hyperpermeability by disrupting endothelia. The cumulative sequences of small doses (fractionated radiotherapy) standard in clinical practice cause it too, but not by endothelial disruption: the mechanisms are unknown. In this study, correlated fluorescent and ultrastructural localisation of a tracer revealed the architecture, fine structure and function of microvessels in mouse AT17 tumours, before and after 42 Gy fractionated radiation. Before irradiation, tumour vascular permeability lay in the normophysiological range defined by the gut and cerebral cortex. A double barrier regulated permeability: vesicular transport through the endothelial wall required approximately 2 h and then the basement membrane charge barrier trapped tracer for 2 h longer. Irradiation abolished the double barrier: tracer passed instantly through both endothelial wall and underlying basement membrane, forming diffusion haloes around microvessels within 2-5 min. Structurally, irradiated tumour microvessels were lined by a continuous and vital endothelium with closed interendothelial junctions; endothelial basement membranes were intact, though loosened. Irradiated endothelia exhibited extremely active membrane motility and intracellular vesicle trafficking. Radiation treatment raised vascular permeability by enhancing transendothelial transcytosis, and by altering the passive filter properties of the subendothelial basement membrane. This type of vascular hyperpermeability should be susceptible to pharmacological modulation.
Debbage
P L
PL
Institute of Anatomy and Histology, University of Innsbruck, Austria. Paul.Debbage@uibk.ac.at
Seidl
S
S
Kreczy
A
A
Hutzler
P
P
Pavelka
M
M
Lukas
P
P
D000230:Adenocarcinoma / Q000098:blood supply* / Q000532:radiotherapy; D000818:Animals; D001485:Basement Membrane / Q000378:metabolism / Q000528:radiation effects / Q000648:ultrastructure; D002199:Capillary Permeability / Q000528:radiation effects*; D019583:Dose Fractionation, Radiation; D004730:Endothelium, Vascular / Q000378:metabolism / Q000528:radiation effects / Q000648:ultrastructure; D037102:Lectins / Q000493:pharmacokinetics*; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000532:radiotherapy; D051379:Mice; D008809:Mice, Inbred C3H; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation
D037102:Lectins