Glp-1r Agonists Improve Cerebrovascular Integrity And Vascular Cognitive Impairment And Dementia (vcid) Beyond Glycemic Control Via Recovery Of Brain Pericyte Function In Diabetic Mice

Abstract

We have previously shown that diabetes causes pericyte-dysfunction that leads to loss of vascular integrity and vascular-induced cognitive impairment and dementia (VCID). Glucagon-like peptide-1(GLP-1), used in the management of type-2 diabetes mellitus, improve cognitive of diabetic patients beyond glycemic control, yet the mechanism is unknown. In the present study, we hypothesis that GLP-1 agonist improves VICD through prevention of diabetes-induced pericytes dysfunction in a non-glucose dependent way. Methods: Control and diabetic mice were randomly assigned for saline or Exendin-4 (GLP-1 agonist 30 ng/kg/day), delivered through osmotic pump over 28 days. Vascular integrity was assessed by measuring cerebrovascular neovascularization indices (Vascular density, tortuosity, and branching density). Cognitive functions were evaluated with Barnes maze and Morrison Water maze. Human brain microvascular pericytes, HBMPCs, were grown in high glucose 25 mM/ sodium palmitate 200 uM (HG/Pal) to mimic diabetic conditions. HBMPCs were treated with/out Exendin-4 and assessed for oxidative stress and angiogenic properties. Results: Diabetic mice treated with GLP-1 agonist showed a significant reduction in all cerebral pathological neovascularization indices (P<0.05). Exendin-4 vascular protective effects was accompanied by significant improvement of the learning and memory functions of diabetic mice (P<0.05). Our results showed that HBMPCs expressed the GLP-1 receptor. Stimulation of HBMPC with GLP-1 against under diabetic conditions restored pericyte functions, decreased diabetes-induced inflammation, oxidative stress, and migration. (P<0.05). Conclusion: Our results provide novel evidence that GLP-1 agonist produces neurovascular protective effects in part through targeting pericytes. Restoration of pericyte functions in diabetes represent a novel therapeutic target for diabetes-induced vascular remodeling and VCID.