VASCULAR WOUND-HEALING AND NEOINTIMA FORMATION INDUCED BY PERIVASCULAR ELECTRIC INJURY IN MICE

Vascular interventions for atherothrombotic disease frequently induce neointima formation, which can contribute to restenosis of blood vesse ls. As the molecular mechanisms of this process remain largely unknown , quantitative models of arterial injury in transgenic animals may be useful to study this process at the genetic level. Here, an injury mod el is proposed in which surgically exposed femoral arteries in mice we re injured perivascularly via a single delivery of an electric current . Transmission electron microscopy, light microscopy, and immunohistoc hemistry revealed that electric injury destroyed all medial smooth mus cle cells, denuded the injured segment of intact endothelium, and tran siently induced platelet-rich mural thrombosis. A vascular wound-heali ng response resulted that was characterized by degradation of the mura l thrombus, transient infiltration of the vessel wall by inflammatory cells, and progressive removal of the necrotic debris. Topographic ana lysis revealed repopulation of the media and accumulation in the neoin tima of smooth muscle cells originating from the uninjured borders and progressing into the necrotic center. Within 3 weeks after injury, a neointima of 0.026 +/- 0.003 mm(2) (n = 7 arteries) was formed that co ntained a maximum of 12 +/- 1 layers of smooth muscle alpha-actin-immu noreactive cells. Evans blue staining in five electrically injured art eries revealed a denuded distance of 2.8 +/- 0.2 mm immediately after injury, which became progressively re-endothelialized from the uninjur ed borders to 2.2 +/- 0.08 mm (P = 0.013 vs freshly injured by analysi s of variance), 0.8 +/- 0.22 mm (P < 0.001), and 0.005 +/- 0.003 mm (P < 0.001) within 2, 7, and 14 days after injury, respectively. Analysi s of 5'-bromo-2'-deoxyuridine incorporation revealed that a maximum 35 +/- 10% endothelial cells proliferated within 2 days after injury and that in the media and neointima, a maximum of, respectively, 12 +/- 2 % and 18 +/- 3% smooth muscle cells proliferated within 2 weeks after injury. Thus, electric injury of arteries provides a model of vascular wound healing with arterial neointima formation and re-endothelializa tion that may be useful for the genetic analysis of its molecular mech anisms in transgenic mice.