Hyperglycemia impairs microglia responding to retinal vasculopathy via enhanced norepinephrine-ADRB2 signaling

Breakdown of the blood-retina barrier is a key event in the progression of retinal vascular diseases. Microglia, the resident immune cells of the retina and central nervous system, respond rapidly to vascular injury, yet how hyperglycemia affects this protective function remains unclear. In this study, we combined intravitreal injection of lipopolysaccharide (LPS) with streptozotocin to mimic both acute inflammation under hyperglycemic conditions. LPS triggered a robust increase in microglia-blood vessel interactions (MVIs), mediated by P2Y12 receptor signaling, as confirmed by both pharmacological inhibition and genetic knockout of P2Y12. Live ex vivo retinal imaging demonstrated that microglial processes rapidly converged on injured vessels within 30 min in a P2Y12-dependent manner. However, four weeks of hyperglycemia significantly blunted this MVI response. We found that hyperglycemia elevated circulating norepinephrine (NE), which infiltrated the retina and suppressed MVIs through activation of microglial β2-adrenergic receptors (ADRB2). Ex vivo imaging further showed that pharmacological ADRB2 activation impaired microglial process convergence to sites of vascular injury. Together, these findings reveal that NE-ADRB2 signaling antagonizes P2Y12-mediated microglial engagement with leaky vessels, contributing to BRB breakdown. This study uncovers a novel neuroimmune-vascular mechanism by which hyperglycemia compromises retinal vascular repair and identifies potential therapeutic targets for retinal vascular disorders.