RESUMO
Hypoxia stimulates angiogenesis through the binding of hypoxia-inducible factors to the hypoxia-response element in the vascular endothelial growth factor (Vegf) promotor. Here, we report that deletion of the hypoxia-response element in the Vegf promotor reduced hypoxic Vegf expression in the spinal cord and caused adult-onset progressive motor neuron degeneration, reminiscent of amyotrophic lateral sclerosis. The neurodegeneration seemed to be due to reduced neural vascular perfusion. In addition, Vegf165 promoted survival of motor neurons during hypoxia through binding to Vegf receptor 2 and neuropilin 1. Acute ischemia is known to cause nonselective neuronal death. Our results indicate that chronic vascular insufficiency and, possibly, insufficient Vegf-dependent neuroprotection lead to the select degeneration of motor neurons.
Assuntos
Hipóxia Celular/genética , Fatores de Crescimento Endotelial/genética , Linfocinas/genética , Neurônios Motores/patologia , Degeneração Neural/genética , Elementos de Resposta/genética , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Animais , Axônios/fisiologia , Sítios de Ligação , Eletrofisiologia , Fatores de Crescimento Endotelial/metabolismo , Humanos , Linfocinas/metabolismo , Camundongos , Camundongos Knockout , Neurônios Motores/fisiologia , Contração Muscular , Fibras Musculares Esqueléticas/patologia , Atrofia Muscular/genética , Atrofia Muscular/patologia , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neuropilina-1 , Nervos Periféricos/patologia , Regiões Promotoras Genéticas , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Fatores de Crescimento/genética , Receptores de Fatores de Crescimento/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular , Deleção de Sequência , Medula Espinal/fisiologia , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
Dominant mutations in ubiquitously expressed transfer RNA (tRNA) synthetase genes cause axonal peripheral neuropathy, accounting for at least six forms of Charcot-Marie-Tooth (CMT) disease. Genetic evidence in mouse and Drosophila models suggests a gain-of-function mechanism. In this study, we used in vivo, cell typespecific transcriptional and translational profiling to show that mutant tRNA synthetases activate the integrated stress response (ISR) through the sensor kinase GCN2 (general control nonderepressible 2). The chronic activation of the ISR contributed to the pathophysiology, and genetic deletion or pharmacological inhibition of Gcn2 alleviated the peripheral neuropathy. The activation of GCN2 suggests that the aberrant activity of the mutant tRNA synthetases is still related to translation and that inhibiting GCN2 or the ISR may represent a therapeutic strategy in CMT.
Assuntos
Doença de Charcot-Marie-Tooth/metabolismo , Glicina-tRNA Ligase/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Estresse Fisiológico , Tirosina-tRNA Ligase/metabolismo , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Animais , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/fisiopatologia , Modelos Animais de Doenças , Feminino , Deleção de Genes , Genes Dominantes , Glicina-tRNA Ligase/genética , Masculino , Camundongos , Camundongos Mutantes , Neurônios Motores/fisiologia , Biossíntese de Proteínas , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Medula Espinal/fisiopatologia , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/genética , Estresse Fisiológico/fisiologia , Transcriptoma , Tirosina-tRNA Ligase/genéticaRESUMO
Proper vascular regulation is of paramount importance for the control of blood flow to tissues. In particular, the regulation of peripheral resistance arteries is essential for several physiological processes, including control of blood pressure, thermoregulation and increase of blood flow to central nervous system and heart under stress conditions such as hypoxia. Arterial tone is regulated by the periarterial autonomic nervous plexus, as well as by endothelium-dependent, myogenic and humoral mechanisms. Underscoring the importance of proper vascular regulation, defects in these processes can lead to diseases such as hypertension, orthostatic hypotension, Raynaud's phenomenon, defective thermoregulation, hand-foot syndrome, migraine and congestive heart failure. Here, we review the molecular mechanisms controlling the development of the periarterial nerve plexus, retrograde and localized signalling at neuro-effector junctions, the molecular and cellular mechanisms of vascular regulation and adult plasticity and maintenance of periarterial innervation. We particularly highlight a newly discovered role for vascular endothelial growth factor in the structural and functional maintenance of arterial neuro-effector junctions. Finally, we discuss how defects in neuronal vascular regulation can lead to disease.