A novel PDGF receptor inhibitor-eluting stent attenuates in-stent neointima formation in a rabbit carotid model

Abstract

A novel drug-eluting stent (DES) is required to target vascular smooth muscle cells (SMCs) without harming endothelial cells (ECs). Platelet-derived growth factor (PDGF) is critical for the proliferation and migration of SMCs. Sunitinib [a PDGF receptor (PDGFR) tyrosine kinase inhibitor]-eluting stents may therefore inhibit neointimal formation. The aim of the present study was to examine the stent-based delivery of sunitinib in a rabbit carotid model; in addition, the effects of sunitinib were evaluated in vitro. Local administration of sunitinib markedly reduced neointimal formation without delaying re-endothelialization in the carotid artery model. In vitro, sunitinib inhibited SMC proliferation; however, no effects were observed on ECs. Sunitinib caused necrosis of SMCs. In addition, sunitinib attenuated PDGF-stimulated SMC migration in a scratch wound assay and inhibited α-SMA cytoskeleton polymerization. Furthermore, sunitinib inhibited PDGF-induced phosphorylation of extracellular signal-regulated kinase in vitro and in vivo. Therefore, this novel DES may be a potential strategy for the treatment of vascular disorders.

Drug-eluting stent specifically designed to target vascular smooth muscle cell phenotypic modulation attenuated restenosis through the YAP pathway

“…2B). Activation of the PDGF receptor was observed in our previous publication 3 mo after BMS implantation (8). We hypothesized that various growth factors that are released after mechanical expansion might be crucial for SMC The detailed mechanisms underlying the effects of SFES on SMC phenotypic modulation require an indepth investigation before its clinical application.…”

“…After sorafenib (catalog no. 8705, Cell Signaling Technology) treatment, MTT assays were performed as previously described to determine SMC and REC proliferation (8).…”

“…Moreover, SRF can interact with other cofactors to promote SMC differentiation. Among them, myocardin (Myocd) is one of the most powerful SRF cofactors (8,10). In the present study, we used the PDGF receptor inhibitor sorafenib to fabricate a new DES and demonstrated the effect of a sorafenib-eluting stent (SFES) on in-stent restenosis.…”

The role of extracellular vesicles in neointima formation post vascular injury

“…It is believed that, at the site of injury, activated ECs, platelets, monocytes and leukocytes express and/or secrete pro-inflammatory molecules such as E-and P-selectin, IL-6, IL-8, platelet-derived growth factor (PDGF), transforming growth factor beta 1 (TGF-β1) and basic fibroblast growth factor (bFGF) thereby stimulating local inflammation and VSMC dedifferentiation, proliferation and migration -cellular processes that are all crucial for the development of intimal hyperplasia (Figure 1) [26,[34][35][36][37][38][39][40][41][42][43][44]. It has previously been shown that targeting those growth factors and/or their receptors in vivo affects the development of both venous and arterial neointimal hyperplasia [45][46][47][48]. Early inward remodelling appears to be predictive of subsequent VGF [49] and limiting intimal hyperplasia in both ex vivo and in vivo studies has been demonstrated as a potentially successful approach to improving graft patency [50,51].…”

RhoA inhibitor-eluting stent attenuates restenosis by inhibiting YAP signaling

“…Coated stents were prepared as we previously reported. 14 The RhoA inhibitor rhosin (Merck, Darmstadt, Germany) dissolved in 100 mL of ethanol was mixed with Muko jelly (Jiangsu Province Jianerkang Medical Dressing Co, Ltd, Jintan, China) to a final concentration of 2 mg/g of jelly. Each balloon-mounted stent (diameter, 2 mm; length, 20 mm) was individually dipped in rhosin jelly to produce a thin stent coating weighing approximately 0.015 g. The stents were air dried to completely evaporate the solvent for 24 hours.…”