Abstract
The phenotypic switch of vascular smooth muscle cells (VSMCs) plays a pivotal role in the development of vascular disorders, such as atherosclerosis, stenosis and restenosis, after vascular intervention. In our previous study, n-butylidenephthalide (BP) was reported to have anti-proliferating and apoptotic effects on VSMCs. The purpose of the current study is to further investigate its role in platelet-derived growth factor (PDGF)-induced VSMC phenotypic modulation in an arteriovenous fistula model. In vitro, we observed that BP inhibited the PDGF-induced cytoskeleton reorganization of the VSMCs. The enhanced expression of vimentin and collagen, as well as the migration ability induced by PDGF, were also inhibited by BP. By cell cycle analysis, we found that BP inhibited the PDGF-induced VSMCs proliferation and arrested the VSMCs in the G0/G1 phase. In an arteriovenous fistula rat model, the formation of stenosis, which was coupled with a thrombus, and the expression of vimentin and collagen in VSMCs, were also inhibited by administration of BP, indicating that BP inhibited the PDGF-induced phenotypic switch and the migration of VSMCs. Besides, the inhibitory effects of BP on the phenotypic switch were found to accompany the activated 5’ AMP-activated protein kinase (AMPK) as well as the inhibited phosphorylation of mTOR. Knockdown of AMPK by gene silencing conflicted the effects of BP and further exacerbated the PDGF-induced VSMCs phenotypic switch, confirming the modulating effect that BP exerted on the VSMCs by this pathway. These findings suggest that BP may contribute to the vasculoprotective potential in vasculature.
Highlights
The vascular smooth muscles (VSMCs) within the tunica media are characterized by remarkable phenotypic plasticity [1]
We have demonstrated that BP can inhibit restenosis in a rat balloon-injured carotid artery model through inducing the apoptosis directly on VSMCs
We further explored the novel findings that the phenotypic switch of VSMCs, induced by platelet-derived growth factor (PDGF), can be inhibited by BP—both in vitro and in an arteriovenous fistula rat model
Summary
The vascular smooth muscles (VSMCs) within the tunica media are characterized by remarkable phenotypic plasticity [1]. The phenotypic switch of VSMCs is a fundamental step in developing vascular pathologies, such as neointimal hyperplasia and restenosis, after the intervention of percutaneous transluminal angioplasty (PTA) or the establishment of an arteriovenous fistula (AVF). The dedifferentiation of VSMCs can be stimulated by the released growth factors and inflammatory cytokines, such as PDGF, IFN-γ and TNF-α, after vascular injury. PDGF has been reported as the most potent mitogens that cause the dedifferentiation of VSMCs via activating variable intracellular signal pathways, including the PI3K/Akt, Rho and mTOR pathways [2,3]. To inhibit the PDGF-stimulated VSMCs’ phenotypic switch may reduce the development of neointimal hyperplasia and stenosis
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.
