Functional inhibitors of acid sphingomyelinase are clinically used as anti-depressants since ~60 years. Here, we show that acid sphingomyelinase inhibition by the antidepressants amitriptyline, fluoxetine and desipramine protects from ischemia/reperfusion and elicits a profound brain remodeling response with increased angiogenesis, improved blood-brain barrier integrity, reduced brain leukocyte infiltration and increased neuronal survival. Angiogenesis is promoted by small extracellular vesicles with bona fide characteristics of exosomes, which are released from endothelial cells and which constitute an elegant target for the amplification of stroke recovery.