Effect of VEGF coating and intra-arterial injection of mesenchymal stem cells on neointima formation after endovascular stenting in a rabbit model

OBJECTIVE: The rates of thromboembolic events are highest within the first few days of intracranial stent placement and before complete endothelialization has occurred. Accelerating the rate of neointima formation may be a strategy to reduce thromboembolic events. This study was performed to evaluate the efficacy of vascular endothelial growth factor (VEGF) embedded in a poly(lactic-co-glycolic acid) (PLGA) coating in conjunction with mesenchymal stem cells (MSCs) to improve neointima formation after stent placement. METHODS: Endovascular stents were coated with VEGF/PLGA or PLGA alone (control 1) or left uncoated (control 2), and protein quantification was performed both before and after a mock endovascular deployment process. A total of 23 New Zealand White rabbits then underwent endovascular implantation of stents coated with VEGF/PLGA, followed by an intra-arterial microcatheter injection of MSCs; stents coated with VEGF/PLGA without MSC injection (vehicle alone); stents coated with PLGA alone without MSC injection (vehicle alone); or uncoated stents without MSC injection (vehicle alone). After stent deployment on day 0 and prior to euthanasia on day 3, animals underwent optical coherence tomography (OCT), so that the degree of neointima formation over the stent struts as well as thrombus formation could be evaluated. Scanning electron microscopy (SEM) was also performed after euthanasia. OCT and SEM images were both scored by observers blinded to treatment group. RESULTS: Stents coated with VEGF/PLGA contained a significantly larger amount of protein than the stents coated with PLGA alone or uncoated stents, and there was no significant loss of protein after the mock delivery process. In vivo, VEGF/PLGA-coated stents with MSC injection demonstrated superior measurements of the neointimal area, neointimal ratio, stent-strut neointimal coverage ratio, and maximum neointimal thickness on OCT compared to those for the uncoated stent at 3 days. VEGF/PLGA-coated stents with MSCs also showed significantly improved scores on SEM and a large, though not statistically significant, reduction in the variability of thrombus formation compared to that with uncoated stents at 3 days (p = 0.06). CONCLUSIONS: This short-term study demonstrates that coating stents with VEGF embedded in PLGA, along with an intra-arterial injection of MSCs, improves neointimal coverage and may reduce thrombus formation. Follow-up studies are required to assess the long-term consequences of VEGF and MSC administration, as well as to elucidate the potential mechanism of their effect.