Diabetes-mediated middle cerebral artery remodeling is restored by linagliptin: Interaction with the vascular smooth muscle cell endothelin system

IntroductionEndothelin-1 (ET-1) mediates cerebrovascular remodeling in vascular smooth muscle layer of the middle cerebral arteries (MCA) in type-2 diabetic Goto-Kakizaki (GK) rats. While metformin, oral glucose lowering agent, prevent/restores vascular remodeling and reduce systemic and local ET-1 levels whether this effect was specific to metformin remained unknown. Our working hypotheses were 1) linagliptin, a DPP-IV inhibitor, can reverse diabetes-mediated cerebrovascular remodeling and this is associated with decreased ET-1, and 2) linagliptin prevents the high glucose induced increase in ET-1 and ET receptors in brain vascular smooth muscle cells (bVSMCs).MethodsDiabetic and non-diabetic GK rats were treated with linagliptin (4 weeks). MCAs were fixed in buffered 4% paraformaldehyde and used for morphometry. Human bVSMCs incubated in normal glucose (5.5 mM)/high glucose (25 mM) conditions were treated with the linagliptin (100 nM; 24 h). ET-1 secretion and ET receptors were measured in media and cell lysate respectively. Immunostaining was performed for ET-A and ET-B receptor. ET receptors were also measured in cells treated with ET-1 (100 nM) and linagliptin.ResultsLinagliptin treatment regressed vascular remodeling of MCAs in diabetic animals but had no effect on blood glucose. bVSMCs in normal/high glucose condition did not show any significant difference in ET-1 secretion or ET-A and ET-B receptor expression. ET-1 treatment in high glucose condition significantly increased the ET-A receptors and this effect was inhibited by linagliptin.ConclusionsLinagliptin is effective in reversing established pathological cerebrovascular remodeling associated with diabetes. Attenuation of the ET system could be a pleiotropic effect of linagliptin that provides vascular protection.