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Ischemic stroke is a leading cause of death and disability worldwide with effective acute thrombolytic treatments. However, brain repair mechanisms related to spontaneous or rehabilitation-induced recovery are still under investigation, and little is known about the molecules involved. The present study examines the potential role of angiogenin (ANG), a known regulator of cell function and metabolism linked to neurological disorders, focusing in the neurogenic subventricular zone (SVZ). Angiogenin expression was examined in the mouse SVZ and in SVZ-derived neural stem cells (NSCs), which were exposed to exogenous ANG treatment during neurosphere formation as well as in other neuron-like cells (SH-SY5Y). Additionally, male C57Bl/6 mice underwent a distal permanent occlusion of the middle cerebral artery to study endogenous and exercise-induced expression of SVZ-ANG and neuroblast migration. Our results show that SVZ areas are rich in ANG, primarily expressed in DCX+ neuroblasts but not in nestin+NSCs. In vitro, treatment with ANG increased the number of SVZ-derived NSCs forming neurospheres but could not modify SH-SY5Y neurite differentiation. Finally, physical exercise rapidly increased the amount of endogenous ANG in the ipsilateral SVZ niche after ischemia, where DCX-migrating cells increased as part of the post-stroke neurogenesis process. Our findings position for the first time ANG in the SVZ during post-stroke recovery, which could be linked to neurogenesis.

Background: Rehabilitation therapy is the only available treatment for stroke survivors presenting neurological deficits; however, the underlying molecules and mechanisms associated with functional/motor improvement during rehabilitation are poorly understood.Objective: Our aim is to study the modulation of angiogenin and endothelial progenitor cells (EPCs) as repair-associated factors in a cohort of stroke patients and mouse models of rehabilitation after cerebral ischemia.Methods: The clinical study included 18 ischemic strokes admitted to an intensive rehabilitation therapy (IRT) unit, 18 non-ischemic controls and brain samples from three deceased patients. Angiogenin and EPCs were measured in blood obtained before and up to 6 months after IRT together with an extensive evaluation of the motor/functional status. In parallel, C57BL/6 mice underwent middle cerebral artery occlusion, and the pasta matrix reaching-task or treadmill exercises were used as rehabilitation models. Angiogenin RNA expression was measured after 2 or 12 days of treatment together with cell counts from EPCs cultures.Results: Brain angiogenin was identified in both human and mouse tissue, whereas serum levels increased after 1 month of IRT in association with motor/functional improvement. EPC populations were increased after stroke and remained elevated during follow-up after IRT. The mouse model of rehabilitation by the task-specific pasta matrix exercise increased the number of EPCs at 2 days and increased angiogenin expression after 12 days of rehabilitation.Conclusions: Angiogenin and EPCs are modulated by rehabilitation after cerebral ischemia, suggesting that both angiogenin and EPCs could serve as biomarkers of improvement during rehabilitation or future therapeutic targets.