Local delivery of thalidomide to inhibit neointima formation in rat model with artery injury

Abstract

Objective: To observe the effect of local administration of thalidomide on neointimal formation after balloon-induced carotid artery injury in rats.

Methods: Forty-eight male Sprague-Dawley rats were randomly divided into 3 groups (n = 16): Sham operation group (group A), alone operation group (group B) and Thalidomide group (group C). The carotid arteries of group B and group C were injured by a conventional percutaneous transluminal coronary angioplasty (PTCA) balloon catheter. Group C was treated by local delivery of thalidomide, and group B did not receive thalidomide. The arteries of group A were not injured. Seven and 14 days after balloon injury, rats were sacrificed. Serum concentrations of vascular endothelial growth factor (VEGF) and tumor necrosis factor-α (TNF-α) were measured using enzyme-linked immunosorbent assay (ELISA). Neointima area, lumen area, macrophage infiltration and local expression of VEGF were measured using morphometric and immunohistochemical analyses. Real-time reverse transcriptase polymerase chain reaction (RT-PCR) was used to examine VEGF mRNA expression.

Results: The VEGF levels were significantly increased in group B than in group C at 7 days (4.82 ± 0.17 pg/mL vs 0.98 ± 0.1 pg/mL, P < 0.01) and 14 days (6.3 ± 0.16 pg/mL vs 1.03 ± 0.09 pg/mL, P < 0.01). The TNF-α levels were also significantly increased in group B than in group C at 7 days (83 ± 1.01 pg/mL vs 76.37 ± 0.75 pg/mL, P < 0.01) and 14 days (84.06 ± 1.11 pg/mL vs 78.46 ± 0.94 pg/mL, P < 0.01). However, the area of neointimal formation was significantly reduced in group C than in group B at 14 days (0.07± 0.01 mm² vs 0.12± 0.04 mm², P < 0.01). Macrophage infiltration and local expression of VEGF in the injured arteries were significantly reduced in group C than in group B at 14 days. VEGF mRNA expression was significantly reduced in Group C than in group B at 14 days (6.3 ± 0.16 vs 1.02 ± 0.1, P < 0.01).

Conclusions: Thalidomide, which is a specific VEGF inhibitor, significantly inhibited neointimal hyperplasia and vascular restenosis after balloon injury to the carotid artery in rats, thus potentially providing a novel method for the prevention and treatment of restenosis, especially in-stent restenosis.

Keywords: Neointimal hyperplasia; Restenosis; Thalidomide; Vascular endothelial growth factor.