Local application of rapamycin inhibits neointimal hyperplasia in experimental vein grafts

Rapamycin is an immunosuppressive agent which also exhibits marked antiproliferative properties. Rapamycin coated stents have been demonstrated to suppress restenosis in experimental and clinical studies of percutaneous coronary catheter intervention. We investigated whether rapamycin can reduce neointima formation in a mouse model of vein graft disease. C57BL6J mice underwent interposition of the inferior vena cava from isogenic donor mice into the common carotid artery using a previously described cuff technique. In the treatment group, 100 μg or 200 μg of rapamycin was applied locally in pluronic gel. The control group did not receive local treatment. Grafts were harvested at 1, 2, 4, and 6 weeks and underwent morphometric analysis as well as immunohistochemical analysis. In grafted veins without treatment (controls), median intimal thickness was 9.6 (6.4 to 29)μm, 11.9 (7.9 to 39.9)μm, 46.6 (12.4 to 57.7)μm, and 57.5 (32.5 to 71.1)μm after 1, 2, 4, and 6 weeks, respectively. Treatment with 100 μg or 200 μg rapamycin showed a dose dependant reduction of intimal thickness. In the 200 μg rapamycin treatment group the intimal thickness was 4.3 (3.4 to 5.6)μm, 3.8 (3.2 to 6.3)μm, 17.1 (4.8 to 63)μm, and 33.9 (11.3 to 80.3)μm after 1, 2, 4, and 6 weeks, respectively. This difference of intimal thickness of 200 μg treated animals compared with controls was statistically significant at 1 and 2 weeks. Immunohistochemically the reduction of intimal thickness was associated with a decreased amount of infiltration of CD-8 positive cells and a decreased amount of metallothionein positive cells in the rapamycin treated grafts. We conclude that perivascular application of rapamycin inhibits neointimal hyperplasia of vein grafts in a mouse model. These results suggest that rapamycin may have a therapeutic potential for the treatment of vein graft disease.