Fluvastatin and vascular endothelial growth factor Containing Resins Promote Angiogenesis and Arteriogenesis

Many patients with chronic limb threatening ischemia rely on neovascularization. Statins and vascular endothelial growth factor (VEGF) stimulate neovascularization. We hypothesized that locally delivered TentaGel (TG) resins containing VEGF-165A or fluvastatin would increase neovascularization in hindlimb ischemia and their combination would be most effective.

Hydrogel resins were loaded with fluvastatin or VEGF-165A. Endothelial angiogenesis and proliferation were examined with free VEGF-165A, fluvastatin, resin, or resin bound VEGF-165A and/or fluvastatin. In hindlimb ischemia, TG resin-bound VEGF-165A, fluvastatin-bound resin, or a combination were injected into rat hindlimbs. Doppler flow was measured at pre and postoperative days 1, 3, 7 and 14. On day 14, the vastus was stained for arteriogenesis and the gastrocnemius for angiogenesis.

In vitro, hydrogel resins took up VEGF-165A surrogate and fluvastatin. Resins released fluvastatin at 10% per 24 h. Unloaded resin had no effect on endothelial cells (ECs). Both free and resin-bound fluvastatin or VEGF-165A promoted EC proliferation and tubule formation. In vivo, blood flow at day 14 with untreated or empty resin showed partial recovery of blood flow, while TG resin-bound fluvastatin returned flow to preoperative levels. The combination increased flow more than fluvastatin alone, and resin-bound VEGF-165A alone had the greatest increase in flow. Resin-bound fluvastatin, resin-bound VEGF-165A, or both increased angiogenesis and arteriogenesis.

In vitro, both free and resin-bound fluvastatin and VEGF-165A equally promoted EC proliferation and tubule formation. In vivo, neovascularization and blood flow improved with VEGF-165A or fluvastatin-bound resins. Resin-bound VEGF-165A was strongest in vivo and warrants further study.