RESUMO
To date, various human disease models in small fish-such as medaka (Oryzias lapties)-have been developed for medical and pharmacological studies. Although genetic and environmental homogeneities exist, disease progressions can show large individual differences in animal models. In this study, we established an intact in vivo angiographic approach and explored vascular networks in the telencephalon of wild-type adult medaka using the spectral-domain optical coherence tomography. Our approach, which required neither surgical operations nor labeling agents, allowed to visualize blood vessels in medaka telencephala as small as about 8 µm, that is, almost the size of the blood cells of medaka. Besides, we could show the three-dimensional microvascular distribution in the medaka telencephalon. Therefore, the intact in vivo imaging via optical coherence tomography can be used to perform follow-up studies on cerebrovascular alterations in metabolic syndrome and their associations with neurodegenerative disease models in medaka.
Assuntos
Microvasos/diagnóstico por imagem , Oryzias/anatomia & histologia , Telencéfalo/irrigação sanguínea , Tomografia de Coerência Óptica/métodos , Animais , Angiografia Cerebral , Angiografia por Tomografia Computadorizada , Modelos Animais , Telencéfalo/diagnóstico por imagemRESUMO
Angiogenesis and neurogenesis are tightly coupled during embryonic brain development. However, little is known about how these two processes interact. We show that nascent blood vessels actively contact dividing neural stem cells by endothelial filopodia in the ventricular zone (VZ) of the murine ventral telencephalon; this association is conserved in the human ventral VZ. Using mouse mutants with altered vascular filopodia density, we show that this interaction leads to prolonged cell cycle of apical neural progenitors (ANPs) and favors early neuronal differentiation. Interestingly, pharmacological experiments reveal that ANPs induce vascular filopodia formation by upregulating vascular endothelial growth factor (VEGF)-A in a cell-cycle-dependent manner. This mutual relationship between vascular filopodia and ANPs works as a self-regulatory system that senses ANP proliferation rates and rapidly adjusts neuronal production levels. Our findings indicate a function of vascular filopodia in fine-tuning neural stem cell behavior, which is the basis for proper brain development.
Assuntos
Células-Tronco Neurais/metabolismo , Neurogênese , Pseudópodes/metabolismo , Telencéfalo/irrigação sanguínea , Animais , Ciclo Celular , Diferenciação Celular , Proliferação de Células , Endotélio Vascular/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/citologia , Neurônios/citologia , Pseudópodes/ultraestrutura , Telencéfalo/ultraestrutura , Imagem com Lapso de Tempo , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND AND PURPOSE: The subcallosal artery [SCA, a branch of the anterior communicating artery (ACoA)] is not well described in the literature. However, the memory disorders that can occur after surgical repair of ruptured ACoA aneurysms might be related to infarction of the SCA. The objective of the present study was to perform a thorough anatomical assessment of the SCA. METHODS: The study was carried out over a 6-month period in a University Hospital's anatomy laboratory, using brains extracted from human cadavers. The brains were injected with colored neoprene latex and dissected to study the SCA's origin, path, termination, diameter, length, and vascularized territories. RESULTS: 21 cadaveric specimens were studied. The mean ± standard deviation diameter and length of the SCA were 0.83 ± 0.57 mm and 38.14 ± 25.11 mm, respectively. The predominantly vascularized territories were the paraterminal gyrus (100%), the parolfactory gyrus (78.95%), the rostrum (84.21%) and genu (78.95%) of the corpus callosum, the lamina terminalis (78.95%), the anterior commissure (63.16%), the anterior cingulate gyrus (47.37%), and the fornix (26.32%). When the SCA supplied the fornix and the anterior cingulate gyrus, it was significantly longer and broader (p < 0.05). CONCLUSION: Anatomic knowledge of the SCA is crucial-especially for the treatment of ACoA aneurysms.
Assuntos
Artéria Cerebral Anterior/anatomia & histologia , Aneurisma Intracraniano/cirurgia , Microcirurgia/métodos , Telencéfalo/irrigação sanguínea , Cadáver , Dissecação/métodos , HumanosRESUMO
The neocortex contains glutamatergic excitatory neurons and γ-aminobutyric acid (GABA)ergic inhibitory interneurons. Extensive studies have revealed substantial insights into excitatory neuron production. However, our knowledge of the generation of GABAergic interneurons remains limited. Here we show that periventricular blood vessels selectively influence neocortical interneuron progenitor behavior and neurogenesis. Distinct from those in the dorsal telencephalon, radial glial progenitors (RGPs) in the ventral telencephalon responsible for producing neocortical interneurons progressively grow radial glial fibers anchored to periventricular vessels. This progenitor-vessel association is robust and actively maintained as RGPs undergo interkinetic nuclear migration and divide at the ventricular zone surface. Disruption of this association by selective removal of INTEGRIN ß1 in RGPs leads to a decrease in progenitor division, a loss of PARVALBUMIN and SOMATOSTATIN-expressing interneurons, and defective synaptic inhibition in the neocortex. These results highlight a prominent interaction between RGPs and periventricular vessels important for proper production and function of neocortical interneurons.
Assuntos
Interneurônios/citologia , Neocórtex/irrigação sanguínea , Neocórtex/embriologia , Células-Tronco Neurais/citologia , Telencéfalo/irrigação sanguínea , Telencéfalo/embriologia , Animais , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Feminino , Idade Gestacional , Proteínas de Fluorescência Verde/metabolismo , Integrina beta1/metabolismo , Interneurônios/metabolismo , Eminência Mediana/irrigação sanguínea , Eminência Mediana/embriologia , Eminência Mediana/metabolismo , Camundongos , Camundongos Transgênicos , Neocórtex/metabolismo , Células-Tronco Neurais/metabolismo , Neuroglia/citologia , Neuroglia/metabolismo , Parvalbuminas/metabolismo , Gravidez , Área Pré-Óptica/irrigação sanguínea , Área Pré-Óptica/embriologia , Área Pré-Óptica/metabolismo , Proteínas Recombinantes/metabolismo , Somatostatina/metabolismo , Telencéfalo/metabolismoRESUMO
BACKGROUND: The brain vascular system arises from the perineural vascular plexus (PNVP) which sprouts radially into the neuroepithelium and subsequently branches off laterally to form a secondary plexus in the subventricular zone (SVZ), the subventricular vascular plexus (SVP). The process of SVP formation remains to be fully elucidated. We investigated the role of Foxc1 in early stage vascular formation in the ventral telencephalon. RESULTS: The Foxc1 loss of function mutant mouse, Foxc1(ch/ch) , showed enlarged telencephalon and hemorrhaging in the ventral telencephalon by embryonic day 11.0. The mutant demonstrated blood vessel dilation and aggregation of endothelial cells in the SVZ after the invasion of endothelial cells through the radial path, which lead to failure of SVP formation. During this early stage of vascular development, Foxc1 was expressed in endothelial cells and pericytes, as well as in cranial mesenchyme surrounding the neural tube. Correspondingly, abnormal deposition pattern of basement membrane proteins around the vessels and increased strong Vegfr2 staining dots were found in the aggregation sites. CONCLUSIONS: These observations reveal an essential role for Foxc1 in the early stage of vascular formation in the telencephalon.
Assuntos
Circulação Cerebrovascular/fisiologia , Embrião de Mamíferos , Fatores de Transcrição Forkhead/metabolismo , Telencéfalo , Animais , Embrião de Mamíferos/irrigação sanguínea , Embrião de Mamíferos/embriologia , Fatores de Transcrição Forkhead/genética , Camundongos , Camundongos Mutantes , Telencéfalo/irrigação sanguínea , Telencéfalo/embriologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/biossíntese , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
Simultaneous generation of neural cells and that of the nutrient-supplying vasculature during brain development is called neurovascular coupling. We report on a transgenic mouse with impaired transforming growth factor ß (TGFß)-signalling in forebrain-derived neural cells using a Foxg1-cre knock-in to drive the conditional knock-out of the Tgfbr2. Although the expression of FOXG1 is assigned to neural progenitors and neurons of the telencephalon, Foxg1(cre/+);Tgfbr2(flox/flox) (Tgfbr2-cKO) mutants displayed intracerebral haemorrhage. Blood vessels exhibited an atypical, clustered appearance were less in number and displayed reduced branching. Vascular endothelial growth factor (VEGF) A, insulin-like growth factor (IGF) 1, IGF2, TGFß, inhibitor of DNA binding (ID) 1, thrombospondin (THBS) 2, and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) 1 were altered in either expression levels or tissue distribution. Accordingly, human umbilical vein endothelial cells (HUVEC) displayed branching defects after stimulation with conditioned medium (CM) that was derived from primary neural cultures of the ventral and dorsal telencephalon of Tgfbr2-cKO. Supplementing CM of Tgfbr2-cKO with VEGFA rescued these defects, but application of TGFß aggravated them. HUVEC showed reduced migration towards CM of mutants compared with controls. Supplementing the CM with growth factors VEGFA, fibroblast growth factor (FGF) 2 and IGF1 partially restored HUVEC migration. In contrast, TGFß supplementation further impaired migration of HUVEC. We observed differences along the dorso-ventral axis of the telencephalon with regard to the impact of these factors on the phenotype. Together these data establish a TGFBR2-dependent molecular crosstalk between neural and endothelial cells during brain vessel development. These findings will be useful to further elucidate neurovascular interaction in general and to understand pathologies of the blood vessel system such as intracerebral haemorrhages, hereditary haemorrhagic telangiectasia, Alzheimers disease, cerebral amyloid angiopathy or tumour biology.
Assuntos
Encéfalo/metabolismo , Neovascularização Fisiológica , Neurônios/metabolismo , Proteínas Serina-Treonina Quinases/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Movimento Celular , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patologia , Meios de Cultivo Condicionados , Fator 2 de Crescimento de Fibroblastos/metabolismo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Neurônios/patologia , Pericitos/metabolismo , Pericitos/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Via Secretória , Telencéfalo/irrigação sanguínea , Telencéfalo/metabolismo , Telencéfalo/patologia , Fator de Crescimento Transformador beta/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
The aim of this study was to detect structural, spatial and quantitative changes of cellular elements of midbrain paranigral nucleus (PNN) and telencephalic anterior cingulate area (ACA) under different conditions of circulatory hypoxia. PNN anteriormedial part and ACA layers V-VI were examined in adult rats 7 days (n=4) after an occlusion of both common carotid arteries as well as in intact (1st control, n=4) and sham-operated animals (2nd control, n=4). In histological the sections, stained with Nissl cresyl violet, and using the methods of glial fibrillary acidic protein and an Ibal-protein detection, the proportions of unmodified, hypochromic, pyknomorphic neurons and ghost cells were determined as well as the numbers of astrocytes, oligodendrocytes, microgliocytes and endotheliocytes. Cell body area of neurons and gliocytes, and the distance between cell bodies and capillaries were measured, a gliocyte-neuronal index was calculated. It was found that brain cellular elements that survive different conditions of a circulatory hypoxia underwent a range of pathological changes. Neurons were in process of nuclear pyknosis, lysis and transformation into the ghost cells. The cells within the hypoxia nuclear zone were prone to death or pyknosis. The neurons located outside the area of hypoxia which were affected only by a humoral impact of reactions of the glutamate-calcium cascade, frequently underwent acute swelling. Microgliocyte reaction in the form of poorly expressed increase in their number and structural signs of activation was an early diffuse manifestation of a prosencephalic focal hypoxia. Endotheliocyte proliferation 7 days after of ischemic challenge was not associated with a chain of cascade reactions and was observed only in the hypoxia focus. Concentration of viable neurons and astrocytes near blood capillaries, as well as an increase in the number of satellite form gliocytes is an adaptation mechanism and a condition for the survival of cells during various types of brain exposure to ischemia.
Assuntos
Doenças das Artérias Carótidas/patologia , Hipóxia Encefálica/patologia , Mesencéfalo/patologia , Neurônios/patologia , Telencéfalo/patologia , Animais , Astrócitos/patologia , Cálcio/metabolismo , Capilares/patologia , Doenças das Artérias Carótidas/metabolismo , Morte Celular , Células Endoteliais/patologia , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Ácido Glutâmico/metabolismo , Masculino , Mesencéfalo/irrigação sanguínea , Mesencéfalo/metabolismo , Microglia/patologia , Neurônios/metabolismo , Ratos , Ratos Wistar , Telencéfalo/irrigação sanguínea , Telencéfalo/metabolismoRESUMO
Mutations in the human NOTCH3 gene cause CADASIL syndrome (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). CADASIL is an inherited small vessel disease characterized by diverse clinical manifestations including vasculopathy, neurodegeneration and dementia. Here we report two mutations in the zebrafish notch3 gene, one identified in a previous screen for mutations with reduced expression of myelin basic protein (mbp) and another caused by a retroviral insertion. Reduced mbp expression in notch3 mutant embryos is associated with fewer oligodendrocyte precursor cells (OPCs). Despite an early neurogenic phenotype, mbp expression recovered at later developmental stages and some notch3 homozygous mutants survived to adulthood. These mutants, as well as adult zebrafish carrying both mutant alleles together, displayed a striking stress-associated accumulation of blood in the head and fins. Histological analysis of mutant vessels revealed vasculopathy, including: an enlargement (dilation) of vessels in the telencephalon and fin, disorganization of the normal stereotyped arrangement of vessels in the fin, and an apparent loss of arterial morphological structure. Expression of hey1, a well-known transcriptional target of Notch signaling, was greatly reduced in notch3 mutant fins, suggesting that Notch3 acts via a canonical Notch signaling pathway to promote normal vessel structure. Ultrastructural analysis confirmed the presence of dilated vessels in notch3 mutant fins and revealed that the vessel walls of presumed arteries showed signs of deterioration. Gaps in the arterial wall and the presence of blood cells outside of vessels in mutants indicated that compromised vessel structure led to hemorrhage. In notch3 heterozygotes, we found elevated expression of both notch3 itself and target genes, indicating that specific alterations in gene expression due to partial loss of Notch3 function might contribute to the abnormalities observed in heterozygous larvae and adults. Our analysis of zebrafish notch3 mutants indicates that Notch3 regulates OPC development and mbp gene expression in larvae, and maintains vascular integrity in adults.
Assuntos
Vasos Sanguíneos/metabolismo , Receptores Notch/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Animais , Apoptose , Vasos Sanguíneos/crescimento & desenvolvimento , Vasos Sanguíneos/patologia , Vasos Sanguíneos/fisiopatologia , Padronização Corporal/genética , Hemorragia/metabolismo , Hemorragia/patologia , Hemorragia/fisiopatologia , Heterozigoto , Humanos , Larva/metabolismo , Mutação/genética , Proteína Básica da Mielina/genética , Proteína Básica da Mielina/metabolismo , Neurogênese , Oligodendroglia/citologia , Oligodendroglia/metabolismo , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor Notch3 , Receptores Notch/genética , Telencéfalo/irrigação sanguínea , Telencéfalo/metabolismo , Telencéfalo/patologia , Telencéfalo/fisiopatologia , Vasodilatação , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genéticaRESUMO
Neural crest (NC) cells originate from the neural folds and migrate into the various embryonic regions where they differentiate into multiple cell types. A population of cephalic neural crest-derived cells (NCDCs) penetrates back into the developing forebrain to differentiate into microvascular pericytes, but little is known about when and how cephalic NCDCs invade the telencephalon and differentiate into pericytes. Using a transgenic mouse line in which NCDCs are genetically labeled with enhanced green fluorescent protein (EGFP), we observed that NCDCs started to invade the telencephalon together with endothelial cells from embryonic day (E) 9.5. A majority of NCDCs located in the telencephalon expressed pericyte markers, that is, PDGFRß and NG2, and differentiated into pericytes around E11.5. Surprisingly, many of the NC-derived pericytes express p75, an undifferentiated NCDC marker at E11.5, as well as NCDCs in the mesenchyme. At the same time, a minor population of NCDCs that located separately from blood vessels in the telencephalon were NG2-negative and some of these NCDCs also expressed p75. Proliferation and differentiation of pericytes appeared to occur in a specific mesenchymal region where blood vessels penetrated into the telencephalon. These results indicate that (i) NCDCs penetrate back into the telencephalon in parallel with angiogenesis, (ii) many NC-derived pericytes may be still in pre-mature states even though after differentiation into pericytes in the early developing stages, (iii) a small minority of NCDCs may retain undifferentiated states in the developing telencephalon, and (iv) a majority of NCDCs proliferate and differentiate into pericytes in the mesenchyme around the telencephalon.
Assuntos
Diferenciação Celular/fisiologia , Movimento Celular/fisiologia , Crista Neural/embriologia , Pericitos/fisiologia , Telencéfalo/embriologia , Fatores Etários , Animais , Bromodesoxiuridina , Contagem de Células , Proteínas de Fluorescência Verde/metabolismo , Imuno-Histoquímica , Hibridização In Situ , Camundongos , Camundongos Transgênicos , Crista Neural/citologia , Pericitos/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Telencéfalo/irrigação sanguíneaRESUMO
Vascular-specific growth factor angiopoietin-2 (Ang2) is mainly involved during vascular network setup. Recently, Ang2 was suggested to play a role in adult neurogenesis, affecting migration and differentiation of adult neuroblasts in vitro. However, to date, no data have reported an effect of Ang2 on neurogenesis during embryonic development. As we detected Ang2 expression in the developing cerebral cortex at embryonic day E14.5 and E16.5, we used in utero electroporation to knock down Ang2 expression in neuronal progenitors located in the cortical ventricular zone (VZ) to examine the role of Ang2 in cortical embryonic neurogenesis. Using this strategy, we showed that radial migration from the VZ toward the cortical plate of Ang2-knocked down neurons is altered as well as their morphology. In parallel, we observed a perturbation of intermediate progenitor population and the surrounding vasculature. Taken together, our results show for the first time that, in addition to its role during brain vasculature setup, Ang2 is also involved in embryonic cortical neurogenesis and especially in the radial migration of projection neurons.
Assuntos
Angiopoietina-2/fisiologia , Neurogênese/fisiologia , Telencéfalo/embriologia , Telencéfalo/crescimento & desenvolvimento , Angiopoietina-2/genética , Animais , Animais Recém-Nascidos , Linhagem Celular Tumoral , Movimento Celular/genética , Movimento Celular/fisiologia , Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/embriologia , Córtex Cerebral/crescimento & desenvolvimento , Feminino , Técnicas de Silenciamento de Genes/métodos , Camundongos , Neurogênese/genética , Neurônios/citologia , Neurônios/fisiologia , Gravidez , Telencéfalo/irrigação sanguíneaRESUMO
The orphan G protein-coupled receptor (GPCR) GPR124/tumor endothelial marker 5 is highly expressed in central nervous system (CNS) endothelium. Here, we show that complete null or endothelial-specific GPR124 deletion resulted in embryonic lethality from CNS-specific angiogenesis arrest in forebrain and neural tube. Conversely, GPR124 overexpression throughout all adult vascular beds produced CNS-specific hyperproliferative vascular malformations. In vivo, GPR124 functioned cell-autonomously in endothelium to regulate sprouting, migration, and developmental expression of the blood-brain barrier marker Glut1, whereas in vitro, GPR124 mediated Cdc42-dependent directional migration to forebrain-derived, vascular endothelial growth factor-independent cues. Our results demonstrate CNS-specific angiogenesis regulation by an endothelial receptor and illuminate functions of the poorly understood adhesion GPCR subfamily. Further, the functional tropism of GPR124 marks this receptor as a therapeutic target for CNS-related vascular pathologies.
Assuntos
Neovascularização Fisiológica , Tubo Neural/irrigação sanguínea , Prosencéfalo/irrigação sanguínea , Receptores Acoplados a Proteínas G/metabolismo , Animais , Vasos Sanguíneos/anormalidades , Barreira Hematoencefálica/metabolismo , Movimento Celular , Desenvolvimento Embrionário , Células Endoteliais/fisiologia , Endotélio Vascular/embriologia , Endotélio Vascular/metabolismo , Deleção de Genes , Transportador de Glucose Tipo 1/metabolismo , Mesencéfalo/irrigação sanguínea , Mesencéfalo/embriologia , Mesencéfalo/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Tubo Neural/embriologia , Tubo Neural/metabolismo , Prosencéfalo/embriologia , Prosencéfalo/metabolismo , Receptores Acoplados a Proteínas G/genética , Rombencéfalo/irrigação sanguínea , Rombencéfalo/embriologia , Rombencéfalo/metabolismo , Telencéfalo/irrigação sanguínea , Telencéfalo/embriologia , Telencéfalo/metabolismoRESUMO
Prevailing notions of cerebral vascularization imply that blood vessels sprout passively into the brain parenchyma from pial vascular plexuses to meet metabolic needs of growing neuronal populations. Endothelial cells, building blocks of blood vessels, are thought to be homogeneous in the brain with respect to their origins, gene expression patterns and developmental mechanisms. These current notions that cerebral angiogenesis is regulated by local environmental signals contrast with current models of cell-autonomous regulation of neuronal development. Here we demonstrate that telencephalic angiogenesis in mice progresses in an orderly, ventral-to-dorsal gradient regulated by compartment-specific homeobox transcription factors. Our data offer new perspectives on intrinsic regulation of angiogenesis in the embryonic telencephalon, call for a revision of the current models of telencephalic angiogenesis and support novel roles for endothelial cells in brain development.
Assuntos
Endotélio Vascular/embriologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Proteínas de Homeodomínio/metabolismo , Telencéfalo/irrigação sanguínea , Telencéfalo/embriologia , Animais , Padronização Corporal/fisiologia , Circulação Cerebrovascular/fisiologia , Embrião de Mamíferos , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Feminino , Proteínas de Homeodomínio/genética , Técnicas In Vitro , Camundongos , Camundongos Knockout , Camundongos Mutantes , Neovascularização Fisiológica/fisiologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Organogênese/fisiologia , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados/genética , Fatores de Transcrição Box Pareados/metabolismo , Gravidez , Receptor TIE-2/genética , Receptor TIE-2/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Fator Nuclear 1 de Tireoide , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
BACKGROUND AND PURPOSE: Stroke induced by middle cerebral artery occlusion (MCAO) causes long-term formation of new striatal neurons from stem/progenitor cells in the subventricular zone (SVZ). We explored whether MCAO leads to hypoxia, changes in vessel density, and angiogenesis in the ipsilateral SVZ and adjacent striatum, and determined the relation between the migrating neuroblasts and the vasculature. METHODS: Adult rats were subjected to 2 hours of MCAO. Hypoxia was studied by injecting Hypoxyprobe-1 during MCAO or 6 weeks later. Vessel density and length was estimated using stereology. New cells were labeled with 5'-bromo-2'deoxyuridine (BrdU) during weeks 1 and 2 or 7 and 8 after MCAO, and angiogenesis was assessed immunohistochemically with antibodies against BrdU and endothelial cell markers. Distance from neuroblasts to nearest vessel was measured using confocal microscopy. RESULTS: The ischemic insult caused transient hypoxia and early, low-grade angiogenesis, but no damage or increase of vascular density in the SVZ. Angiogenesis was detected during the first 2 weeks in the dorsomedial striatum adjacent to the SVZ, which also showed long-lasting increase of vascularization. At 2, 6, and 16 weeks after MCAO, the majority of neuroblasts migrated through this area toward the damage, closely associated with blood vessels. CONCLUSIONS: The vasculature plays an important role for long-term striatal neurogenesis after stroke. During several months, neuroblasts migrate close to blood vessels through an area exhibiting early vascular remodeling and persistently increased vessel density. Optimizing vascularization should be an important strategy to promote neurogenesis and repair after stroke.
Assuntos
Movimento Celular , Artérias Cerebrais/fisiopatologia , Neovascularização Fisiológica , Células-Tronco , Acidente Vascular Cerebral/fisiopatologia , Telencéfalo/fisiopatologia , Animais , Contagem de Células , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Artérias Cerebrais/patologia , Corpo Estriado/irrigação sanguínea , Corpo Estriado/patologia , Corpo Estriado/fisiopatologia , Modelos Animais de Doenças , Progressão da Doença , Hipóxia Encefálica/fisiopatologia , Infarto da Artéria Cerebral Média/fisiopatologia , Ventrículos Laterais , Masculino , Regeneração Nervosa , Plasticidade Neuronal , Neurônios/patologia , Ratos , Ratos Wistar , Recuperação de Função Fisiológica , Células-Tronco/patologia , Telencéfalo/irrigação sanguínea , Telencéfalo/patologia , Fatores de TempoRESUMO
OBJECTIVE: The aim of this study was to correlate changes in regional cerebral blood flow (rCBF) to the degree of cerebral vasospasm in the canine two-hemorrhage model of subarachnoid hemorrhage (SAH). METHODS: SAH was induced in 13 adult beagle dogs using the two-hemorrhage model. Eleven beagle dogs served as controls. Angiography of the basilar artery and measurements of rCBF with colored microspheres were performed on days 1 and 8. Diameter of the basilar artery was calculated at equidistant points from the angiogram. RESULTS: In controls, basilar artery diameter (mm) and rCBF (mL/min/g) were equal on days 1 and 8. In the SAH group, basilar artery diameter decreased significantly (1.27 +/- 0.17 [mean +/- SD]-0.84 +/- 0.15 mm). rCBF decreased significantly (P < .05) in the cerebrum (1.69 +/- 0.54 [mean +/- SD]-1.06 +/- 0.45 mL/min/g), cerebellum (1.18 +/- 0.40-0.80 +/- 0.32 mL/min/g), and brain stem (0.81 +/- 0.33-0.51 +/- 0.21 mL/min/g). However, decrements in CBF were not correlated to the reduction in vessel caliber in the corresponding vascular territory. CONCLUSION: Induced SAH in the canine model produces a significant impairment in rCBF irrespective of the degree of vasospasm of large cerebral vessels. The findings support the presumptive role of the microvasculature in regard to delayed cerebral ischemia after SAH.
Assuntos
Circulação Cerebrovascular , Hemorragia Subaracnóidea/fisiopatologia , Vasoespasmo Intracraniano/fisiopatologia , Animais , Artéria Basilar/patologia , Velocidade do Fluxo Sanguíneo , Isquemia Encefálica/etiologia , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Tronco Encefálico/irrigação sanguínea , Cerebelo/irrigação sanguínea , Cães , Microcirculação , Microesferas , Modelos Animais , Circulação Renal , Telencéfalo/irrigação sanguínea , Vasoespasmo Intracraniano/complicações , Vasoespasmo Intracraniano/patologiaRESUMO
Melatonin plays a key role in a variety of important physiological functions including influencing cerebral blood vessels. Therefore, in the present study, we have identified the existence of melatonin receptors and test the effect of melatonin on hydrogen peroxide-induced endothelial nitric oxide synthase (eNOS) expression in bovine cerebral arteries. The results indicate that mt1A melatonin receptor mRNA is expressed in bovine cerebral arteries. The relative levels of mt1A melatonin receptor mRNA expression in anterior, posterior, middle and vertebral cerebral arteries were compared. The data show the highest and lowest levels of mRNA expressions in the middle and vertebral cerebral arteries, respectively. The maximal number (B(max)) of different types of melatonin receptors in various regions of cerebral arteries were identified and further characterized by using the selective 2-[(125)I] iodomelatonin binding assay. Saturation studies revealed that the binding represented a single site of high affinity binding for the melatonin receptor with the highest and lowest binding capacities in the middle and vertebral arteries, respectively. In order to elaborate the functional significance of melatonin in cerebral blood vessels, hydrogen peroxide- induced induction in eNOS protein level and phosphorylation of calcium/calmodulain-dependent protein kinase II (phospho-CaMKII) were demonstrated in the bovine isolated cerebral arteries with these effect being abolished by melatonin. This is the first evidence showing expression of mt1A melatonin receptor in the bovine cerebral arteries. However, further studies are necessary to delineate the role of melatonin and its receptors in regulating physiology of the cerebral vessels.
Assuntos
Artérias Cerebrais/enzimologia , Peróxido de Hidrogênio/farmacologia , Melatonina/fisiologia , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/genética , Receptores de Melatonina/metabolismo , Telencéfalo/irrigação sanguínea , Animais , Bovinos , Feminino , Peróxido de Hidrogênio/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/biossíntese , RNA Mensageiro/metabolismoRESUMO
Peri-infarct increase of vascular density has been observed in animals and in humans with ischemic stroke. Increased peri-infarct vascular density correlates with improved functional outcome after stroke. We hypothesized that pre-treatment with estradiol will increase post-ischemic peri-infarct capillary density in a rat model of transient ischemic stroke. Estradiol, compared to placebo, augmented post-ischemic peri-infarct vascular density by 22% 10 days after stroke. Recovery of forelimb function was not improved with estradiol treatment on day three and nine post-stroke. Loss of estradiol may limit repair in the peri-infarct region by limiting angiogenesis, but functional significance in stroke recovery requires further investigation.
Assuntos
Indutores da Angiogênese/farmacologia , Infarto Encefálico/tratamento farmacológico , Artérias Cerebrais/efeitos dos fármacos , Estradiol/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Indutores da Angiogênese/uso terapêutico , Animais , Infarto Encefálico/fisiopatologia , Capilares/efeitos dos fármacos , Capilares/fisiologia , Artérias Cerebrais/fisiopatologia , Modelos Animais de Doenças , Estradiol/uso terapêutico , Feminino , Membro Anterior/inervação , Membro Anterior/fisiopatologia , Microcirculação/efeitos dos fármacos , Microcirculação/fisiologia , Córtex Motor/irrigação sanguínea , Córtex Motor/efeitos dos fármacos , Córtex Motor/fisiopatologia , Neovascularização Fisiológica/fisiologia , Paresia/tratamento farmacológico , Paresia/etiologia , Paresia/fisiopatologia , Ratos , Ratos Wistar , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologia , Acidente Vascular Cerebral/fisiopatologia , Telencéfalo/irrigação sanguínea , Telencéfalo/efeitos dos fármacos , Telencéfalo/fisiopatologia , Resultado do TratamentoRESUMO
Cerebral blood flow pressure-passivity results when pressure autoregulation is impaired, or overwhelmed, and is thought to underlie cerebrovascular injury in the premature infant. Earlier bedside observations suggested that transient periods of cerebral pressure-passivity occurred in premature infants. However, these transient events cannot be detected reliably by intermittent static measurements of pressure autoregulation. We therefore used continuous bedside recordings of mean arterial pressure (MAP; from an indwelling arterial catheter) and cerebral perfusion [using the near-infrared spectroscopy (NIRS) Hb difference (HbD) signal) to detect cerebral pressure-passivity in the first 5 d after birth in infants with birth weight <1500 g. Because the Hb difference (HbD) signal [HbD = oxyhemoglobin (HbO2) - Hb] correlates with cerebral blood flow (CBF), we used coherence between MAP and HbD to define pressure-passivity. We measured the prevalence of pressure-passivity using a pressure-passive index (PPI), defined as the percentage of 10-min epochs with significant low-frequency coherence between the MAP and HbD signals. Pressure-passivity occurred in 87 of 90 premature infants, with a mean PPI of 20.3%. Cerebral pressure-passivity was significantly associated with low gestational age and birth weight, systemic hypotension, and maternal hemodynamic factors, but not with markers of maternal infection. Future studies using consistent serial brain imaging are needed to define the relationship between PPI and cerebrovascular injury in the sick premature infant.
Assuntos
Pressão Sanguínea/fisiologia , Estado Terminal , Homeostase/fisiologia , Recém-Nascido Prematuro/fisiologia , Telencéfalo/irrigação sanguínea , Adolescente , Adulto , Transtornos Cerebrovasculares/diagnóstico , Transtornos Cerebrovasculares/fisiopatologia , Feminino , Humanos , Recém-Nascido , MasculinoRESUMO
OBJECTIVE: To explore middle cerebral artery (MCA) and anterior cerebral artery (ACA) blood flow responses to superimposed acute hypoxemia in growth-restricted fetuses with and without established brain-sparing flow during basal conditions. MATERIAL AND METHODS: 47 term fetuses suspected of growth restriction were exposed to an oxytocin challenge test with simultaneous cardiotocography and Doppler velocimetry in the umbilical artery, MCA and ACA. The MCA-to-ACA pulsatility index (PI) ratio was calculated during basal conditions, contractions and relaxations. Basal brain-sparing flow was defined as an MCA-to-umbilical artery PI ratio of<1.08, de novo brain-sparing flow in the MCA as an MCA PI decrease with> or =1 standard deviation during uterine contractions or relaxations compared with basal measurements, and de novo brain-sparing flow in the ACA as an ACA PI decrease with > or =1 standard deviation. Non-parametric statistical tests were used with P<0.05 considered significant. RESULTS: MCA and ACA PI were both significantly lower in the brain-sparing flow group (N=8) during basal conditions (P< or =0.01). During the oxytocin challenge test, MCA and ACA PI both decreased in the non-brain-sparing flow group (N=39) (P< or =0.02) but not in the brain-sparing flow group (P> or =0.4). The MCA-to-ACA PI ratio remained unchanged in both groups. de novo brain-sparing flow calculations revealed no preferential flow to any cerebral artery. CONCLUSION: Cerebral circulatory responses to acute hypoxemia are synchronized in the middle and anterior cerebral arteries without any preferential regional flow distribution.
Assuntos
Circulação Cerebrovascular/fisiologia , Retardo do Crescimento Fetal/fisiopatologia , Hipóxia/fisiopatologia , Fluxo Sanguíneo Regional/fisiologia , Contração Uterina/fisiologia , Adulto , Artéria Cerebral Anterior/diagnóstico por imagem , Artéria Cerebral Anterior/efeitos dos fármacos , Artéria Cerebral Anterior/fisiopatologia , Circulação Cerebrovascular/efeitos dos fármacos , Feminino , Humanos , Artéria Cerebral Média/diagnóstico por imagem , Artéria Cerebral Média/efeitos dos fármacos , Artéria Cerebral Média/fisiopatologia , Ocitocina , Gravidez , Fluxo Sanguíneo Regional/efeitos dos fármacos , Telencéfalo/irrigação sanguínea , Ultrassonografia Doppler , Ultrassonografia Pré-Natal , Contração Uterina/efeitos dos fármacosRESUMO
UNLABELLED: The aim of this study was to determine if the results of visual and quantitative EEG (QEEG) parameters reveal a correlation with mental impairment in subcortical vascular dementia (SVD), one of the most frequent causes of cognitive impairment in the elderly. In SVD, like in Alzheimer's disease disturbances were found in cholinergic transmission. The cholinergic deficit as manifested in changes of synaptic potentials is reflected in EEG signals. MATERIAL: 31 patients with probable SVD (according to NINCDS-AIREN and T. Erkinjuntii's criteria) and mean age 72.3 yrs;(M--43%, F--57%) and 14 healthy control subjects with mean age of 72.3 yrs (M-57%, F-43%). According to the Mini Mental Scale Examination (MMSE) the SVD group was divided into two subgroups with mild and moderate dementia, their EEGs being recorded with a Medelec and Neuroscan 4.2 system. Visual EEG findings were classified with the use of eight-degree scale of pathological changes by the presence of slow waves. Then QEEGs were made. The following parameters were calculated: alpha/slow wave power ratios, the mean wave frequency in all and in some selected derivations. RESULTS: A significant difference was found between QEEGs in SVD subgroups with mild and moderate dementia (p<0.05), but there was no significant difference between visual EEGs. A significant correlation between QEEG parameters such as alpha/slow wave ratio or mean wave frequency and mental impairment (according to MMSE results) was found (p<0.001), but there was no significant correlation between degree of EEG abnormalities in visual analysis and MMSE results. CONCLUSION: Only QEEGs are correlated with mental impairment in SVD. Visual EEG technique as a less precise tool does not reflect the mental impairment in SVD due to cholinergic deficit.
Assuntos
Demência Vascular/diagnóstico , Demência Vascular/fisiopatologia , Avaliação da Deficiência , Eletroencefalografia/métodos , Transtornos Neurocognitivos/diagnóstico , Transtornos Neurocognitivos/fisiopatologia , Acetilcolina/deficiência , Idoso , Idoso de 80 Anos ou mais , Núcleo Basal de Meynert/metabolismo , Núcleo Basal de Meynert/patologia , Núcleo Basal de Meynert/fisiopatologia , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/fisiopatologia , Demência Vascular/psicologia , Progressão da Doença , Eletroencefalografia/normas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fibras Nervosas Mielinizadas/metabolismo , Fibras Nervosas Mielinizadas/patologia , Transtornos Neurocognitivos/etiologia , Testes Neuropsicológicos , Estimulação Luminosa , Valor Preditivo dos Testes , Transmissão Sináptica/fisiologia , Telencéfalo/irrigação sanguínea , Telencéfalo/patologia , Telencéfalo/fisiopatologiaRESUMO
PURPOSE: To determine the usefulness of brain perfusion SPECT for evaluating the severity and progression of Alzheimer's disease (AD). METHODS: Eighty-four AD patients were included. At entry, 99mTc-HMPAO-SPECT, the Mini Mental State Examination (MMSE), Mental Function Impairment Scale (MENFIS), and the Raven Colored Progression Matrix (RCPM) were performed for all 84 patients. During the follow-up periods, two individual MMSE evaluations in 34 patients, two MENFIS evaluations in 30 patients, and two RCPM evaluations in 20 patients were performed. Based on the regions of decreased cerebral blood flow demonstrated on 3D-SSP images of SPECT, the cases were classified as type A (no decrease), type B (decreased blood flow in the parietal or temporal lobe), type C (decreased blood flow in the frontal lobe and parietal or temporal lobe), type Pc (decreased blood flow in posterior cingulate gyrus only), and "other types". The types of decreased blood flow, scores on neuropsychological evaluations, and symptom progression were analyzed. RESULTS: The MENFIS, MMSE, and RCPM scores were poorest in type C patients at entry. The degree of decrease of these scores during the follow-up periods was also greatest in type C. The greatest difference between patients with and without rapid progression in SPECT data of the mild AD patients (MMSE score > or = 24) was in the frontal lobe. CONCLUSION: Decreased blood flow in the frontal lobe of AD patients is correlated not only with reduced cognitive function at the time of the evaluation but with rapid progression in the subsequent clinical course.