Abstract 105: Obesity Induces Vascular Remodeling and Deteriorates Cognitive Function in Mice: Role of Pericytes

Abstract

30 million Americans of the United States population have diabetes. Additional 90 million people in the pre-diabetic stage. Insulin resistance and obesity are the hallmarks of prediabetes. Understanding the effect of obesity on cerebrovasculature is crucial to identify novel therapies to prevent cerebrovascular complications of diabetes including vascular cognitive impairment and dementia. We hypothesize that pericyte dysfunction in prediabetes causes vascular remodeling and pathological neovascularization that leads to vascular cognitive impairment and dementia. Methods, male and female mice were fed regular or a high fat diet (HFD) for 12 weeks. Insulin resistance (IR) was confirmed with a glucose tolerance test. Neovascularization indices were measured (Vascular density, tortuosity, and branching density) to assess cerebral integrity. Pericyte count and basement membrane thickness (BMT) were determined in the cerebral cortex. Learning and memory functions were evaluated using Water maze, Y-maze and novel object recognition (NOR). Pericyte (PC) were grown in high glucose (HG) to mimic prediabetes. Pericytes MMP9 activity, TIMP1 and PDGFR beta internalization were measured. Results, male and female mice fed with HFD showed a significant increase in body weight and IR as indicated by impaired glucose tolerance. 3D reconstructed images of cerebral cortex vasculature showed that HFD significantly increases neovascularization indices (P<0.05, n=5). TEM studies showed an increase in cerebrovascular BMT in HFD mice that was associated with significantly decreased in PCs count and TIMP-1 expression in the cerebral cortex. HFD led to significant deterioration of cognitive memory function in Water maze, Y maze, and NOR. (P<0.05, n=5). MMP9 activity and internalization of PDGFR beta were increased in HG-treated PCs that were accompanied by a decrease in TIMP1 expression. (P<0.05, n=4). Conclusion, obesity-induced pericyte dysfunction is associated with pathological cerebral vessel remodeling and impaired cognitive function. These studies illustrate the crucial role of pericyte dysfunction in prediabetes and identify pericytes as a potential therapeutic target for the treatment of cognitive impairment in diabetes.