RESUMEN
Age-related cerebral blood flow decreases are thought to deteriorate cognition and cause senescence, although the related mechanism is unclear. To investigate the relationships between aging and changes in cerebral blood flow and vasculature, we obtained fluorescence images of young (2-month-old) and old (12-month-old) mice using indocyanine green (ICG). First, we found that the blood flow in old mice's brains is lower than that in young mice and that old mice had more curved pial arteries and fewer pial artery junctions than young mice. Second, using Western blotting, we determined that the ratio of collagen to elastin (related to cerebral vascular wall distensibility) increased with age. Finally, we found that the peak ICG intensity and blood flow index decreased, whereas the mean transit time increased, with age in the middle cerebral artery and superior sagittal sinus. Age-related changes in pial arterial structure and composition, concurrent with the observed changes in the blood flow parameters, suggest that age-related changes in the cerebral vasculature structure and distensibility may induce altered brain blood flow.
Asunto(s)
Envejecimiento/patología , Envejecimiento/fisiología , Arterias Cerebrales/patología , Arterias Cerebrales/fisiopatología , Circulación Cerebrovascular/fisiología , Envejecimiento/metabolismo , Animales , Velocidad del Flujo Sanguíneo , Arterias Cerebrales/metabolismo , Colágeno/metabolismo , Elastina/metabolismo , Verde de Indocianina , Masculino , Ratones Endogámicos BALB C , Imagen Óptica , Seno Sagital Superior/metabolismo , Seno Sagital Superior/patología , Seno Sagital Superior/fisiopatologíaRESUMEN
Exendin-4, an analog of glucagon-like peptide-1, has shown to have beneficial effects on endothelial function, and was recently approved for the treatment of diabetes. In previous studies, we showed that exendin-4 induces angiogenesis in in vitro and ex vivo assays; in this study, we assessed the proangiogenic effects of exendin-4 in vivo using a mouse hindlimb ischemia model. Treatment with exendin-4 for three days mitigated hindlimb and gastrocnemius muscle fiber necrosis. Hindlimb perfusion was determined using indocyanine green fluorescence dynamics that showed, significantly higher blood flow rate to the ischemic hindlimbs in an exendin-4-treated group. Immunohistochemistry assay showed that exendin-4 increased CD31-positive areas in the gastrocnemius muscle of ischemic limbs. Furthermore, treatment of the hindlimbs of ischemic mice with exendin-4 increased vascular endothelial growth factor (VEGF) and phospho-extracellular signal-related kinase (ERK) on western blot analysis. Our data demonstrate that exendin-4 prevents hindlimb ischemic injury by inducing vessels via VEGF angiogenic-related pathways. These findings suggest that exendin-4 has potential as a therapeutic agent for vascular diseases that stimulate angiogenesis.
Asunto(s)
Inductores de la Angiogénesis/uso terapéutico , Isquemia/tratamiento farmacológico , Neovascularización Fisiológica/efectos de los fármacos , Péptidos/uso terapéutico , Ponzoñas/uso terapéutico , Animales , Modelos Animales de Enfermedad , Exenatida , Hemodinámica/efectos de los fármacos , Miembro Posterior/irrigación sanguínea , Miembro Posterior/lesiones , Isquemia/patología , Isquemia/fisiopatología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: Currently used techniques for diagnosing ischemic injury, such as magnetic resonance imaging and computed tomography, are not easily accessible for basic research using small animals due to their high cost and low availability. NEW METHOD: We investigated the dynamic recovery of infarct regions in ischemia-injured brains using indocyanine green (ICG), which is inexpensive and readily available. This dye was used to visualize blood vessels and infarct area, and to measure blood flow after a photothrombotic ischemic operation (PIO). Mice were injected with ICG via the tail vein, and a time-series of fluorescence signal images was acquired before and after PIO. We then applied color codes to arteries and veins in the images and analyzed ICG intensity and dynamics. RESULTS: These time-series stacked images showed changes in pial vessel morphology after PIO. Further, a map of maximum fluorescence intensity showed an infarct in the dorsal cortical region. Changes in the blood flow index and mean transit time were also observed in the infarct region after PIO. COMPARISON WITH EXISTING METHOD(S): Our application of ICG imaging provided a range of information on PIO-induced infarcts in mice with relative ease and in a cost-effective manner. CONCLUSION: Our results show that optical imaging using ICG combined with a time-series analysis of molecular dynamics can be a useful tool for the anatomical and physiological monitoring of cortical ischemia.
Asunto(s)
Isquemia Encefálica/fisiopatología , Encéfalo/fisiopatología , Verde de Indocianina , Imagen Óptica/métodos , Animales , Encéfalo/irrigación sanguínea , Encéfalo/patología , Isquemia Encefálica/patología , Circulación Cerebrovascular/fisiología , Modelos Animales de Enfermedad , Fluorescencia , Masculino , Ratones Endogámicos C57BL , Piamadre/irrigación sanguínea , Piamadre/patología , Piamadre/fisiopatología , Flujo Sanguíneo Regional/fisiologíaRESUMEN
C57BL/6 mice have more cerebral arterial branches and collaterals than BALB/c mice. We measured and compared blood flow dynamics of the middle cerebral artery (MCA) in these two strains, using noninvasive optical imaging with indocyanine green (ICG). Relative maximum fluorescence intensity (Imax) and the time needed for ICG to reach Imax in the MCA of C57BL/c were lower than that in BALB/c mice. Moreover, the mean transit time was significantly lower in C57BL/6 than in BALB/c mice. These data suggest that the higher number of arterial branches and collaterals in C57BL/6 mice yields a lower blood flow per cerebral artery.