RESUMEN
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.
Asunto(s)
Anticuerpos Antiidiotipos/farmacología , Isquemia Encefálica/tratamiento farmacológico , Proteínas Nogo/genética , Receptores de Esfingosina-1-Fosfato/genética , Accidente Cerebrovascular/tratamiento farmacológico , Animales , Encéfalo/efectos de los fármacos , Encéfalo/patología , Isquemia Encefálica/genética , Isquemia Encefálica/inmunología , Isquemia Encefálica/patología , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/patología , Modelos Animales de Enfermedad , Humanos , Ratones , Neovascularización Fisiológica/genética , Neovascularización Fisiológica/inmunología , Neuronas/efectos de los fármacos , Neuronas/patología , Proteínas Nogo/antagonistas & inhibidores , Proteínas Nogo/inmunología , Tractos Piramidales/efectos de los fármacos , Tractos Piramidales/patología , Recuperación de la Función/genética , Receptores de Esfingosina-1-Fosfato/antagonistas & inhibidores , Receptores de Esfingosina-1-Fosfato/inmunología , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/inmunología , Traumatismos de la Médula Espinal/patología , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/inmunología , Accidente Cerebrovascular/patologíaRESUMEN
The distinct organization of the brain's vasculature ensures the adequate delivery of oxygen and nutrients during development and adulthood. Acute and chronic pathological changes of the vascular system have been implicated in many neurological disorders including stroke and dementia. Here, we describe a fast, automated method that allows the highly reproducible, quantitative assessment of distinct vascular parameters and their changes based on the open source software Fiji (ImageJ). In particular, we developed a practical guide to reliably measure aspects of growth, repair and maturation of the brain's vasculature during development and neurovascular disease in mice and humans. The script can be used to assess the effects of different external factors including pharmacological treatments or disease states. Moreover, the procedure is expandable to blood vessels of other organs and vascular in vitro models.