Introduction: Obesity is a leading public health problem in the US. More than one-third of adult are obese. It is closely related to development of the metabolic syndrome, which produces various vascular risk factors, including hyperglycemia, hyperlipidemia, hypertension and low high-density lipoprotein. All these factors increase the risk of developing chronic vascular diseases, particularly cerebral vascular disease. Studies show that patients with metabolic syndrome have a six-fold increase in the risk of developing microvascular infarcts in the brain, which predominantly injure white matter leading to dementia, disability and even death.
Hypothesis: The purpose of this study is to assess the effects of metabolic syndrome on cerebral microvasculature and unveil the molecular mechanisms that regulate these changes.
Methods: Transgenic mice (Tie2-Cre:flox-stop tdtomato plus flox-RiboTAG) were fed with 60%kCal from fat diet to induce metabolic syndrome for 12 weeks at 2 months age and 10%kCal from fat diet was used as control. The volume of cerebral vasculature in white matter was evaluated by reporter gene expression in endothelial cells of Tie2-Cre:flox-stop tdtomato mice. Transcriptomes from cerebral endothelial cells were isolated using Ribotag ribosomal immunoprecipitation technology (Tie2-Cre:flox-RiboTAG). Following ribosomal associated transcriptome isolation, RNA-seq was performed.
Results: Metabolic syndrome results in a significant decrease in white matter vascular volume in both large (30±2.2%, P< 0.04) and micro vessel (23±3.7%, P<0.01). Transcriptional profiling of white matter endothelial cells reveal a difference of expression profile between normal mice and mice with metabolic syndrome. The significant changes in endothelial cell gene expression are associated with the decreased volume of vessels in white matter with metabolic syndrome through changes in angiogenic receptor ligands.
Conclusion: Metabolic syndrome decreases the volumes of large and micro vessels in white matter and significantly changes endothelial cell gene expression. These findings help to develop molecular therapeutic approaches for patients with metabolic syndrome to prevent cerebral microvascular complications including stroke.