Sildenafil Reduces Neointimal Hyperplasia after Angioplasty and Inhibits Platelet Aggregation via Activation of cGMP-dependent Protein Kinase
Abstract
Sildenafil is known to reduce cardiac hypertrophy through cGMP-dependent protein kinase (cGK) activation. Studies have demonstrated that cGK has a central switching role in modulating vascular smooth muscle cell (VSMC) phenotype in response to vascular injury. Here, we aimed to examine the effects of cGK activation by sildenafil on neointimal formation and platelet aggregation. After vascular injury, neointimal hyperplasia in rat carotid arteries was significantly reduced in the sildenafil-treated group. This effect of sildenafil was accompanied by the reduction of viability and migration of VSMCs. Further experiments showed that the increased cGK activity by sildenafil inhibited platelet-derived growth factor-induced phenotype change of VSMCs from a contractile form to a synthetic one. Conversely, the use of cGK inhibitor or gene transfer of dominant-negative cGK reversed the effects of sildenafil, increasing viability of VSMCs and neointimal formation. Interestingly, sildenafil significantly inhibited platelet aggregation induced by ADP or thrombin. This effect was reversed by cGK inhibitor, suggesting that sildenafil inhibits platelet aggregation via cGK pathway. This study demonstrated that sildenafil inhibited neointimal formation and platelet aggregation via cGK pathway. These results suggest that sildenafil could be a promising candidate for drug-eluting stents for the prevention of both restenosis and stent thrombosis.
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