In an effort to elucidate the molecular mechanisms underlying cerebral vascular alteration after stroke, the authors measured the spatial and temporal profiles of blood-brain barrier (BBB) leakage, angiogenesis, vascular endothelial growth factor (VEGF), associated receptors, and angiopoietins and receptors after embolic stroke in the rat. Two to four hours after onset of ischemia, VEGF mRNA increased, whereas angiopoietin 1 (Ang 1) mRNA decreased. Three-dimensional immunofluorescent analysis revealed spatial coincidence between increases of VEGF immunoreactivity and BBB leakage in the ischemic core. Two to 28 days after the onset of stroke, increased expression of VEGF/VEGF receptors and Ang/Tie2 was detected at the boundary of the ischemic lesion. Concurrently, enlarged and thin-walled vessels were detected at the boundary of the ischemic lesion, and these vessels developed into smaller vessels via sprouting and intussusception. Three-dimensional quantitative analysis of cerebral vessels at the boundary zone 14 days after ischemia revealed a significant (P < 0.05) increase in numbers of vessels (n = 365) compared with numbers (n = 66) in the homologous tissue of the contralateral hemisphere. Furthermore, capillaries in the penumbra had a significantly smaller diameter (4.8 +/- 2.0 microm) than capillaries (5.4 +/- 1.5 microm) in the homologous regions of the contralateral hemisphere. Together, these data suggest that acute alteration of VEGF and Ang 1 in the ischemic core may mediate BBB leakage, whereas upregulation of VEGF/VEGF receptors and Ang/Tie2 at the boundary zone may regulate neovascularization in ischemic brain.
A new interventional radiologic procedure was developed for treatment of epiphora. A small-bore, soft-tipped guide wire was introduced through the superior canaliculus and guided under fluoroscopic control through the nasolacrimal drainage system for retrieval through the nasal aperture. A small-bore angioplasty catheter was then introduced in a retrograde direction into the nasolacrimal drainage apparatus and dilated under fluoroscopic control. The procedure was attempted in 18 eyes of 17 patients with moderate to severe epiphora and was technically completed in 16; 13 of these cases demonstrated improvement, with 11 patients showing complete resolution of symptoms. In the three patients whose epiphora did not improve, no worsening of symptoms occurred. These results are preliminary; follow-up ranged from 7 weeks to 6 months. The authors believe that this technique may hold promise in the treatment of epiphora and may obviate the use of more invasive procedures.
Angiogenesis and neurogenesis are coupled processes. Using a coculture system, we tested the hypothesis that cerebral endothelial cells activated by ischemia enhance neural progenitor cell proliferation and differentiation, while neural progenitor cells isolated from the ischemic subventricular zone promote angiogenesis. Coculture of neural progenitor cells isolated from the subventricular zone of the adult normal rat with cerebral endothelial cells isolated from the stroke boundary substantially increased neural progenitor cell proliferation and neuronal differentiation and reduced astrocytic differentiation. Conditioned medium harvested from the stroke neural progenitor cells promoted capillary tube formation of normal cerebral endothelial cells. Blockage of vascular endothelial growth factor receptor 2 suppressed the effect of the endothelial cells activated by stroke on neurogenesis as well as the effect of the supernatant obtained from stroke neural progenitor cells on angiogenesis. These data suggest that angiogenesis couples to neurogenesis after stroke and vascular endothelial growth factor likely mediates this coupling.
The mechanisms underlying cerebral microvascular perfusion deficit resulting from occlusion of the middle cerebral artery (MCA) require elucidation. We, therefore, tested the hypothesis that intravascular fibrin deposition in situ directly obstructs cerebral microcirculation and that local changes in type 1 plasminogen activator inhibitor (PAI-1) gene expression contribute to intravascular fibrin deposition after embolic MCA occlusion. Using laser-scanning confocal microscopy (LSCM) in combination with immunofluorescent staining, we simultaneously measured in three dimensions the distribution of microvascular plasma perfusion deficit and fibrin(ogen) immunoreactivity in a rat model of focal cerebral embolic ischemia (n ϭ 12). In addition, using in situ hybridization and immunostaining, we analyzed expression of PAI-1 in ischemic brain (n ϭ 13). A significant ( p Ͻ 0.05) reduction of cerebral microvascular plasma perfusion accompanied a significant ( p Ͻ 0.05) increase of intravascular and extravascular fibrin deposition in the ischemic lesion. Microvascular plasma perfusion deficit and fibrin deposition expanded concomitantly from the subcortex to the cortex during 1 and 4 hr of embolic MCA occlusion. Threedimensional analysis revealed that intravascular fibrin deposition directly blocks microvascular plasma perfusion. Vascular plugs contained erythrocytes, polymorphonuclear leukocytes, and platelets enmeshed in fibrin. In situ hybridization demonstrated induction of PAI-1 mRNA in vascular endothelial cells in the ischemic region at 1 hr of ischemia. PAI-1 mRNA significantly increased at 4 hr of ischemia. Immunohistochemical staining showed the same pattern of increased PAI-1 antigen in the endothelial cells. These data demonstrate, for the first time, that progressive intravascular fibrin deposition directly blocks cerebral microvascular plasma perfusion in the ischemic region during acute focal cerebral embolic ischemia, and upregulation of the PAI-1 gene in the ischemic lesion may foster fibrin deposition through suppression of fibrinolysis.
Neural progenitor cells in the subventricular zone (SVZ) of the lateral ventricular wall give rise to new neurons throughout rodent life. Ischemic stroke induces angiogenesis and neurogenesis. Using laser capture microdissection (LCM) in combination with microarrays containing approximately 400 known genes associated with stem cells and angiogenesis, we investigated gene profiles of SVZ cells in the adult mouse subjected to middle cerebral artery occlusion. Our data revealed that nonstroke SVZ cells expressed sets of genes that are important for neural progenitor cell proliferation, differentiation, and migration. In addition, stroke SVZ cells expressed many genes involved in neurogenesis during embryonic development but were not detected in nonstroke SVZ cells. Stroke upregulated genes were verified by real-time reverse transcriptase-polymerase chain reaction and immunostaining. These data indicate that adult SVZ cells recapture embryonic molecular signals after stroke and provide insight into the molecular mechanisms, which regulate the biological function of neural progenitor cells in the SVZ of adult rodent brain under physiological and stroke conditions.
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