RESUMO
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.
Assuntos
Anticorpos Anti-Idiotípicos/farmacologia , Isquemia Encefálica/tratamento farmacológico , Proteínas Nogo/genética , Receptores de Esfingosina-1-Fosfato/genética , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Isquemia Encefálica/genética , Isquemia Encefálica/imunologia , Isquemia Encefálica/patologia , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/patologia , Modelos Animais de Doenças , Humanos , Camundongos , Neovascularização Fisiológica/genética , Neovascularização Fisiológica/imunologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Proteínas Nogo/antagonistas & inibidores , Proteínas Nogo/imunologia , Tratos Piramidais/efeitos dos fármacos , Tratos Piramidais/patologia , Recuperação de Função Fisiológica/genética , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidores , Receptores de Esfingosina-1-Fosfato/imunologia , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/patologia , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/patologiaRESUMO
Blood vessels nurture every part of the human body. Consequently, abnormalities in the vasculature are closely associated with a variety of diseases, including cerebral stroke, heart disease, retinopathy, and cancer. Pro- or antiangiogenic therapies can influence these diseases by regulating the growth of new blood vessels from a pre-existing vascular network or dampening excessive blood growth. However, clinical translation of these approaches is slow and challenging. In this review, we discuss recent preclinical approaches to regulate angiogenesis and their potential and risks in a clinical setting.-Rust, R., Gantner, C., Schwab, M. E. Pro- and antiangiogenic therapies: current status and clinical implications.