Nogo-A targeted therapy promotes vascular repair and functional recovery following stroke

Significance Patients suffering from ischemic strokes have limited therapeutic options and are often left with considerable disabilities. To promote neurological recovery, angiogenesis has been proposed as a promising therapeutic target. So far, experimental efforts to enhance vessel growth have almost exclusively focused on vascular growth factor supplementation; this approach has been shown not to be clinically viable due to hemorrhagic risks. Here, we pursued an alternative approach by targeting the guidance molecule Nogo-A, which has been recently shown to inhibit developmental central nervous system angiogenesis. Blockage of the Nogo-A pathway results in restoration of a mature vascular bed within the periinfarct zone. Moreover, we observe enhanced recovery-associated tissue responses and regain of motor functions that strongly correlate with vascular growth. Stroke is a major cause of serious disability due to the brain’s limited capacity to regenerate damaged tissue and neuronal circuits. After ischemic injury, a multiphasic degenerative and inflammatory response is coupled with severely restricted vascular and neuronal repair, resulting in permanent functional deficits. Although clinical evidence indicates that revascularization of the ischemic brain regions is crucial for functional recovery, no therapeutics that promote angiogenesis after cerebral stroke are currently available. Besides vascular growth factors, guidance molecules have been identified to regulate aspects of angiogenesis in the central nervous system (CNS) and may provide targets for therapeutic angiogenesis. In this study, we demonstrate that genetic deletion of the neurite outgrowth inhibitor Nogo-A or one of its corresponding receptors, S1PR2, improves vascular sprouting and repair and reduces neurological deficits after cerebral ischemia in mice. These findings were reproduced in a therapeutic approach using intrathecal anti–Nogo-A antibodies; such a therapy is currently in clinical testing for spinal cord injury. These results provide a basis for a therapeutic blockage of inhibitory guidance molecules to improve vascular and neural repair after ischemic CNS injuries.