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.

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The mouse retina provides an excellent model for studying angiogenesis. Recent advancements in high-throughput microscopy and image analysis provide great tools to visualize and describe the complexity of the retinal vascular architecture in a detailed and comprehensive way. Most developmental studies have focused on only a few parameters mostly in the inner-most layers that do not describe the entirety of the three-dimensional vascular network. Here, we analyzed the entire three-dimensional retinal vascular architecture and its growth and remodeling starting from the age of postnatal day 3 to 4 months in mice. We show plexus specific characteristics of the vasculature in terms of vascular tissue fraction, branching and length of the blood vessels, and distance and distribution between single capillaries. Such detailed knowledge is of particular interest, as it has become apparent that disease-specific mechanisms and treatments affect the retinal vasculature often in a plexus specific way.

Angiogenesis is a key restorative process following stroke but has also been linked to increased vascular permeability and blood brain barrier (BBB) disruption. Previous pre-clinical approaches primarily focused on the administration of vascular endothelial growth factor (VEGF) to promote vascular repair after stroke. Although shown to improve angiogenesis and functional recovery from stroke, VEGF increased the risk of blood brain barrier disruption and bleedings to such an extent that its clinical use is contraindicated. As an alternative strategy, antibodies against the neurite growth inhibitory factor Nogo-A have recently been shown to enhance vascular regeneration in the ischemic central nervous system (CNS); however, their effect on vascular permeability is unknown. Here, we demonstrate that antibody-mediated Nogo-A neutralization following stroke has strong pro-angiogenic effects but does not increase vascular permeability as opposed to VEGF. Moreover, VEGF-induced vascular permeability was partially prevented when VEGF was co-administered with anti-Nogo-A antibodies. This study may provide a novel therapeutic strategy for vascular repair and maturation in the ischemic brain.

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Blood brain barrier (BBB) damage is an important pathophysiological feature of ischemic stroke which significantly contributes to development of severe brain injury and therefore is an interesting target for therapeutic intervention. A popular permanent occlusion model to study long term recovery following stroke is the photothrombotic model, which so far has not been anatomically characterized for BBB leakage beyond the acute phase. Here, we observed enhanced BBB permeability over a time course of 3 weeks in peri-infarct and core regions of the ischemic cortex. Slight increases in BBB permeability could also be seen in the contralesional cortex, hippocampus and the cerebellum at different time points, regions where lesion-induced degeneration of pathways is prominent. Severe damage of tight and adherens junctions and loss of pericytes was observed within the peri-infarct region. Overall, the photothrombotic stroke model reproduces a variety of features observed in human stroke and thus, represents a suitable model to study BBB damage and therapeutic approaches interfering with this process.

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Cross-talk between the peripheral immune system and the central nervous system is important for physiological brain health. T cells are required to maintain normal baseline levels of neural precursor proliferation in the hippocampus of adult mice. We show here that neither T cells, B cells, natural killer cells nor natural killer T cells are required for the increase in hippocampal precursor proliferation that occurs in response to physical exercise. In addition, we demonstrate that a subpopulation of T cells, regulatory T cells, is not involved in maintaining baseline levels of neural precursor proliferation. Even when applied at supraphysiological numbers, populations of both naive and stimulated lymphocytes had no effect on hippocampal precursor proliferation in vitro. In addition, physical activity had no effect on peripheral immune cells in terms of distribution in the bone marrow, lymph nodes or spleen, activation state or chemokine receptor (CXCR4 and CCR9) expression. Together these results suggest that lymphocytes are not involved in translating the peripheral effects of exercise to the neurogenic niche in the hippocampus and further support the idea that the exercise-induced regulation of adult neurogenesis is mechanistically distinct from its baseline control.