Fig 2: Schematic representation of inflammatory circuits in previously radiated arteries. Previously radiated arterial segments exhibited an increased adventitial inflammatory response that was characterized by macrophage accumulation in the vicinity of an expanded of vasa vasorum. Previous studies have associated radiation with activation of the NF-κB pathway (6). The present study identified increased levels of 5-LO in radiated vs. nonradiated arterial segments, and that this enzyme was localized to perivascular adventitial macrophages. The 5-LO enzyme metabolizes arachidonic acid (AA) the LT precursor, LTA4, which is then further metabolized to the chemotactic and proinflammatory LTB4. In radiated arteries, adventitial LTB4 was increased compared with the release from arterial medium. LTB4 transduces proinflammatory effects by means of its high-affinity BLT1 receptor, expressed on macrophages, smooth muscle cells (SMCs), and endothelial cells. Blocking 5-LO/LTB4 signaling may represent a possible therapeutic adjunct to prevent late adverse cardiovascular effects of XRT.

Fig 3: Chronic vascular inflammation and adventitial vasa vasorum expansion in irradiated human arteries. Immunofluorescent staining on the arterial wall is positive for 5-LO in irradiated arteries. A–E) 5-LO–positive cells localized around the expanded vasa vasorum in the adventitia of irradiated (XRT) (C–E), but not in nonirradiated (0 XRT) (A, B) arteries. K–O) Invasion of macrophages into the adventitia was observed in irradiated arteries only. F–J) VWF staining was confined to vasa vasorum in the adventitia of irradiated arteries and not observed in the adventitia of nonirradiated controls from the same patients. Blue fluorescence, DAPI; red fluorescence, 5-LO; green fluorescence, VWF/CD68.