The dipeptidyl peptidase-4 inhibitor Saxagliptin improves function of circulating pro-angiogenic cells from type 2 diabetic patients

Background: Type 2 diabetes (T2D) is associated with reduction and dysfunction of circulating pro-angiogenic cells (PACs). DPP-4 inhibitors, a class of oral agents for T2D, might possess pleiotropic vasculoprotective activities. Herein, we tested whether DPP-4 inhibition with Saxagliptin affects the function of circulating PACs from T2D and healthy subjects. Methods: PACs were isolated from T2D (n = 20) and healthy (n = 20) subjects. Gene expression, clonogenesis, proliferation, adhesion, migration and tubulisation were assessed in vitro by incubating PACs with or without Saxagliptin and SDF-1 alpha. Stimulation of angiogenesis by circulating cells from T2D patients treated with Saxagliptin or other non-incretinergic drugs was assessed in vivo using animal models. Results: Soluble DPP-4 activity was predominant over cellular activity and was successfully inhibited by Saxagliptin. At baseline, T2D compared to healthy PACs contained less acLDL(+) Lectin(+) cells, and showed altered expression of genes related to adhesion and cell cycle regulation. This was reflected by impaired adhesion and clonogenesis/proliferative response of T2D PACs. Saxagliptin +SDF-1 alpha improved adhesion and tube sustaining capacity of PACs from T2D patients. CD14(+) PACs were more responsive to Saxagliptin than CD14(-) PACs. While Saxagliptin modestly reduced angiogenesis by mature endothelial cells, circulating PACs-progeny cells from T2D patients on Saxagliptin treatment displayed higher growth factor-inducible in vivo angiogenetic activity, compared to cells from T2D patients on non-incretinergic regimen. Conclusions: Saxagliptin reverses PACs dysfunction associated with T2D in vitro and improves inducible angiogenesis by circulating cells in vivo. These data add knowledge to the potential pleiotropic cardiovascular effects of DPP-4 inhibition.