Abstract
Background: Sildenafil is widely used to treat erectile dysfunction. Sildenafil inhibits phospho-diesterase 5 (PDE5), thereby increasing cGMP levels in target tissues. The NO-cGMP pathway has been shown to be essential for angiogenesis, vasculogenesis and postnatal neovascularization. Therefore, here we tested the hypothesis that sildenafil might improve neovascularization following ischemia. Methods and results: Hypercholesterolemic ApoE−/− mice, which are characterised by reduced neovascularization in response to ischemia, were treated or not with sildenafil (40 mg/kg/day in water) for the whole duration of the study. Sildenafil was well tolerated by ApoE−/− mice and led to a significant increase of plasmatic cGMP levels compared to controls (13.4±1.9 vs. 4.6±2.6 pmol/mL, p<0.05). After two weeks of treatment, hindlimb ischemia was surgically induced by femoral artery removal. Sildenafil treatment led to a significantly faster rate of blood flow recovery, as assessed by Laser Doppler measurement at day 7 after surgery (55.5% increase, p<0.05). We found that sildenafil treatment is associated with an increased activation of angiogenic transduction pathways such as Akt, p44/42 MAPK, and p38 in ischemic muscles (phosphospecific Western blots). Moreover, sildenafil treatment leads to a significant reduction of oxidative stress in ischemic tissues (nitrotyrosine staining). Endothelial progenitor cells (EPCs) have been shown to participate to postnatal neovascularization. We found that ApoE−/− mice treated with sildenafil have a significant increase in the number of bone marrow EPCs (DiI-AcLDL and FITC-Lectin staining) compared to untreated mice (272±18 vs. 187±17 cells per field, p<0.05). Moreover, the adhesion (19.7±2.1 vs. 10.0±1.9 EPCs per field, p<0.05) and the migratory capacity (28.5±1.8 vs. 15.2±1.3 EPCs per field, p<0.0001) of EPCs are significantly improved in ApoE−/− mice treated with sildenafil. Conclusions: Sildenafil treatment is associated with improved ischemia-induced neovascularization in hypercholesterolemic conditions. The mechanisms involve beneficial effects of sildenafil on angiogenic pathways in ischemic tissues together with an increase in the number and the functional activity of EPCs.
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