Low-dose (7 to 14 Gy) endovascular irradiation (brachytherapy) has been shown to be effective in animal models, for inhibiting the formation of proliferative neointimal lesions after vascular injury. At higher radiation doses (greater than or equal to 28 Gy) an inhibition of negative remodeling or chronic vessel constriction is also seen. Such findings have prompted several clinical trials of vascular brachytherapy for prevention of restenosis after balloon angioplasty and endovascular stenting; preliminary results available in some studies have documented a reduction in restenosis rate. While the suppression of vascular cell cycling has been suggested as one mechanism for the inhibition of neointima, the effects of radiation on arterial cellular functions and the response to vascular injury are still poorly understood. The purpose of the proposed investigation is to study effects of endovascular ionizing radiation on arterial cell, molecular, and physiologic mechanisms regulating: 1) potential changes in functional aspects of arterial biology consequent to ionizing radiation in the presence and absence of angioplasty injury, especially a) vasomotor reactivity and b) thrombogenicity of the luminal surface; and 2) alterations in extracellular matrix content which would influence vessel integrity and architecture. These studies will employ a relevant animal model system, with defined physiologic and pathologic outcomes. With respect to arterial healing events, influences of brachytherapy on thrombosis, re-endothelialization, and extracellular matrix composition will be examined. Determinants of vasomotor function will also be assessed, including effects of brachytherapy on superoxide production, endothelium-dependent and -independent relaxation responses, and nitric oxide synthesis. These studies will therefore determine, using an established pig coronary artery model system, the role of endovascular irradiation in modifying key functional and structural components of the coronary arteries in the presence and absence of a balloon catheter- induced arterial injury and healing response analogous to restenosis. The investigations will thus help fill crucial missing gaps in our knowledge about the new technique of endovascular brachytherapy for restenosis prevention.
