Photochemically Induced Endothelial Injury in the Mouse as a Screening Model for Inhibitors of Vascular Intimal Thickening

From the Department of Pharmacology, Hamamatsu University School of Medicine, Hamamatsu (S.K., K.U., K.K., M.N.), and Japan Immunoresearch Laboratories, Takasaki (A.R.S.), Japan.

Correspondence to Kazuo Umemura, MD, PhD, Department of Pharmacology, Hamamatsu University School of Medicine, 3600 Handa-cho, Hamamatsu, 431-31, Japan. E-mail umemura{at}hama-med.ac.jp

Abstract—We have established a mouse model of intimal thickening and assessed its suitability for experimental studies of intimal thickening. Neointimal formation was observed after endothelial injury by photochemical reaction between transluminal green light and systemically administered rose Bengal, which represents a nonmechanical approach to vessel wall denudation. Intimal thickening began 7 days after endothelial injury, reached a maximum after 21 days, and then remained unchanged for as long as 42 days. Furthermore, as a consequence of neointimal proliferation, the luminal area gradually decreased. The cells in the neointimal layer were identified as smooth muscle cells by immunohistochemical staining with an -actin–specific antibody. Extracellular matrix deposition in the neointima was markedly increased beyond 14 days after injury. Smooth muscle cell proliferation, as measured by pulse labeling of 5-bromo-2'-deoxyuridine, was identified initially in the media 2 days after vessel wall denudation, with the proliferative activity's shifting almost exclusively to the neointima within 7 days. Endothelial regeneration, as indicated by Evans blue staining, was complete within 21 days after injury. To assess the suitability of this model for experimental studies on intimal thickening, the effect of tranilast, an antiallergy drug with a broad spectrum of pharmacological actions on intimal thickening, was investigated. Tranilast (100 mg · kg^-1 · d^-1 PO) significantly (P<0.05) reduced smooth muscle cell proliferation in the neointima and media 7 days after injury and neointimal formation 21 days after injury in treated mice compared with vehicle-treated mice. This simple experimental mouse model is suitable for studying factors promoting or inhibiting intimal thickening after endothelial injury and for developing therapeutic strategies against intimal thickening.

Key Words: mouse • endothelial injury • intimal thickening • smooth muscle cell proliferation • tranilast

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