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.
Highlights
In cases of restenosis after stent implantation, the status of vascular smooth muscle cell (VSMC) is the most important factor in modulating neointimal formation[9]
To see whether sildenafil could affect the vessel wall, we measured the distribution of PDE5 and cyclic guanosine monophosphate (cGMP)-dependent protein kinase (cGK) in various rat organs (Fig. 1a)
We found that PDE5 was expressed strongly in the VSMC layer
Summary
In cases of restenosis after stent implantation, the status of VSMCs is the most important factor in modulating neointimal formation[9]. VSMCs can be divided into two types, contractile and synthetic[12,13] Vessel injury such as stent implantation converts VSMCs from the contractile form to the synthetic one[13]. Several studies have shown that cyclic guanosine monophosphate (cGMP)-dependent kinase (cGK) plays a key role in modulating VSMC phenotype and neointimal formation[14]. (b) In the human heart, the smooth muscle layer of the coronary artery strongly expressed both PDE5 and cGK (n = 10). CGK, a main pathway of PDE5 inhibitors, is highly expressed in platelets[15]. We examined the effects of sildenafil on neointimal formation after balloon injury and its mechanisms of action in VSMCs and platelets
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
