Although postangioplasty and in-stent restenosis remain ominous problems in percutaneous coronary intervention where good animal models of restenosis proneness and resistance are needed. We accidentally discovered that the carotid arteries of the Harlan and Sasco substrains of Sprague-Dawley (SD) rats display drastically different restenosis phenotypes, following balloon-induced endothelial denudation. When subjected to balloon injury, Sasco carotid arteries (CAs) exhibited significantly larger neointimal mass than did Harlan CAs at both day 14 and day 32, as evidenced by a higher intima-to-media ratio and a greater number of intimal cells in Sasco. This was due to greater cell proliferation and to less vigorous apoptosis of Sasco neointima, as assessed by BrdU and TUNEL staining, respectively. At a cellular level, while vascular smooth muscle cells (VSMCs) isolated from Sasco and Harlan CAs were identical in morphology and in propensity to migrate, Sasco VSMCs proliferated more robustly and died far less, suggesting that under the exact same microenvironment, Sasco and Harlan VSMCs respond to growth and noxious stimuli in a drastically different fashion and that Sasco's significantly more robust neointimal proliferation after vascular injury in vivo can be accounted for by these intrinsic differences in VSMCs of these substrains in vitro. Sasco and Harlan SD rats as well as VSMCs from these rats will prove to be powerful tools to study genes involved in the pathogenesis of restenosis.