Pentoxifylline inhibits neointimal formation and stimulates constrictive vascular remodeling after arterial injury

Pentoxifylline (PTX) is a phosphodiesterase inhibitor used in the treatment of peripheral vascular disease, and this agent can suppress inflammatory vascular damage. Inflammation has been implicated in vascular lesion formation, and we examined the effects of PTX in a model of arterial injury. Sprague-Dawley rats were treated with intraperitoneal PTX (75 mg/kg/day) or saline starting 3 days before carotid balloon injury, and killed 24 h or 14 days later. Carotid arteries were analyzed by cross-sectional morphometry, immunostaining for proliferating cell nuclear antigen (PCNA) and subjected to terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL). Moreover, the effects of PTX on vascular smooth-muscle cell (VSMC) migration and production of collagen types I, IV, and VI were examined in vitro. At 14 days after balloon injury, PTX reduced the neointimal area (0.074+/-0.001 vs. 0.172+/-0.003 mm2; p<0.001), media area (0.143+/-0.001 vs. 0.176+/-0.001 mm2; p<0.01), intima/media ratio (0.50+/-0.02 vs. 0.99+/-0.12; p<0.001), and total vessel area (0.601+/-0.010 vs. 0.744+/-0.011 mm2; p<0.01). The lumen area, PCNA expression, and TUNEL were similar in the two treatment groups, whereas the neointimal cell density was increased by PTX (3,476+/-504 cells/mm2 vs. 2,215+/-232 cells/mm2; p<0.05). In vitro, PTX inhibited VSMC production of collagen type I in a concentration-dependent manner and did not influence VSMC migration. We conclude that PTX inhibits neointimal formation and induces constrictive vascular remodeling in the rat model of balloon injury by mechanisms involving decreased VSMC collagen type I production.