Purpose/Objective: A critical issue in the topic of radiation inhibition of restenosis is whether a therapeutic ratio exists between the dose that inhibits restenosis versus the dose which will induce vascular stenosis. Our central unified hypothesis is that the cell initiating and driving vascular restenosis and external vascular remodeling following angioplasty is the same group of cells attributed with inducing arterial stenosis following atherosclerosis - namely the monocyte/macrophage family of inflammatory cells. We have carried out a series of experiments using a rat carotid angioplasty model, with and without irradiation, followed by specific immunohistochemical and cytochemical staining which was applied in a temporal series in order to determine macrophage activity versus smooth muscle cell proliferation.Materials and Methods: We have performed a number of preliminary studies using a technique pioneered by Clowes et al. (1983) Radiation was given immediately post-angioplasty, and was administered over a range of 5-15 Gy. Detailed studies were made at a number of time points (1 day, 1, 2, 3 weeks, 2 and 6 months post-injury). Following sacrifice, a variety of histological/immunocytochemical staining were carried out and analyses were made using an Olympus Cue-3 system.Results: Dramatic changes occurred within 1 week of injury, where macrophages are seen in all layers of the arterial wall. Macrophage-specific stains identified macrophages in a highly nucleated pseudo-intimal region as well as in the media. Platelet-derived growth factor expression also corresponded to these zones of macrophage infiltration. No α-smooth muscle actin was in evidence in these pseudo-intimal cells, but was present in the tunica media. As the neointimal hyperplasia thickened and progressed from 3 weeks to 6 months, SMCs and/or myofibroblasts migrated and proliferated with an accompanying accumulation of PDGF protein. Through actin-staining, smooth muscle cells were identified in the tunica media at 1 week and in the zone of neointimal hyperplasia from 3 weeks to 6 months post-injury. However, infiltrated among the myofibroblast cells were monocytes/macrophages, which were more scattered and intermixed. Following irradiation of doses between 10-15 Gy, angioplastied vessels were inhibited from forming restenotic lesions, and in turn, very few to no inflammatory monocyte/macrophage cells were detected in the walls; there was a relative absence of PDGF at the 2 and 6 month time points.Conclusion: By comparing radiation-induced arterial injury of larger vessels to the above, we postulate that a dose and temporal therapeutic window exists. The mechanism behind radiation-induced injury is postulated to be similar to that of the response to injury of atherosclerosis, except that the radiation dose required is higher and the time for expression following irradiation is longer. Therefore, a therapeutic window exists since the dose required to induce arterial injury per se is higher than that required to inhibit the inflammatory cells induced following angioplasty and the time for expression is longer for radiation-induced larger artery stenosis.