EXPRESS: Brain pericytes bridge and constrict capillaries in a streptozotocin diabetes mouse model.

Diabetes is an established driver of microvascular disease, causing complications such as retinopathy, nephropathy, and neuropathy. However, the mechanisms whereby diabetes disrupts brain microvascular function remain poorly understood. Diabetes is strongly associated with cognitive impairments, including Alzheimer's Disease (AD), in which pericyte pathology is implicated in cerebrovascular dysfunction. Pericytes are critical regulators of blood-brain barrier integrity and capillary blood flow, yet their behavior during early diabetes remains uncharacterized. Using a 14-day streptozotocin (STZ) mouse model of early hyperglycemia, we demonstrate two distinct phenotypic changes in the brain prior to pericyte loss. First, tissue clearing and 3D imaging reveal significantly increased pericyte-vessel bridging across multiple brain regions, including the entorhinal cortex and hippocampus, regions among the earliest and most affected in AD. Second, longitudinal two-photon microscopy demonstrates that brain pericytes constrict capillaries in a manner correlated with blood-glucose levels. Capillary constriction occurs at pericyte soma and is associated with significantly reduced red blood cell velocity. Pericytes exhibiting early constriction predominantly maintain this phenotype rather than transitioning to a bridging state, suggesting these represent distinct disease-associated behaviors. These findings indicate that early pericyte pathology may contribute to cerebrovascular dysfunction in diabetes, with implications for understanding microvascular mechanisms linking diabetes and AD.