Sildenafil induces revascularization after rat hindlimb ischemia in association with resistance arteries outward remodeling.

Abstract

Background: Angiogenesis has a key role in ischemic diseases. Sildenafil inhibits phosphodiesterase 5, increases intracellular cGMP content and thus induces vasodilation. As its effects on the peripheral vasculature in ischemic conditions are unknown, we investigated the consequences of a long-term treatment with Sildenafil on post-ischemic revascularization. Methods and results: In Sildenafil-treated rats (25mg/kg/d) left femoral artery was ligated. After 7 or 21 days, vascular density and blood flow were evaluated in legs and expressed as ischemic (left)/non-ischemic (right) (L/R) leg ratio. At 7 and 21 days, the L/R ratio was 33±2% and 54±9% in controls, respectively. Sildenafil increased this ratio to 47±4% and to 128±11%, respectively. Blood flow and arteriolar density followed the same pattern. At seven days, Sildenafil–induced revascularization was associated with activation of the PI3-kinase-Akt-eNOS pathway. After 21 days, this pathway was down-regulated. HIF1 and VEGF level was not affected by Sildenafil in the ligated leg, despite revascularization suggesting that arteriogenesis predominated over angiogenesis. Indeed, Sildenafil induced outward remodeling (arteriogenesis) in resistance arteries. Conclusion: Chronic Sildenafil increased local blood flow and collateral arteries growth in association with activation of the PI3K-AKT-eNOS pathway after ligature of the femoral artery.