Acute alterations in microvascular basal lamina after subarachnoid hemorrhage

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Object. Aneurysmal subarachnoid hemorrhage (SAH) causes acute and delayed ischemic brain injuries. The mechanisms of acute ischemic injury following SAH are poorly understood, although an acute increase in microvascular permeability has been noted. The integrity of cerebral microvessels is maintained in part by components of basal lamina: collagen IV, elastin, lamina, and so forth. Destruction of basal lamina components by collagenases and matrix metalloproteinases (MMPs), especially MMP-9, has been known to occur in other ischemic models. The authors assessed the integrity of cerebral microvasculature after acute SAH by examining collagen IV and MMP-9 levels and collagenase activity in the microvessels.

Methods. Subarachnoid hemorrhage was induced in rats through endovascular perforation of the intracranial bifurcation of the internal carotid artery. Animals were killed 10 minutes to 48 hours after SAH or sham operation (time-matched controls). Levels of collagen IV and MMP-9 were studied in the microvasculature by performing immunoperoxidase and immunofluorescence staining, and collagenase activity was assessed by in situ zymography.

Little change occurred in collagen IV and MMP-9 immunostaining or collagenase activity at 10 minutes or 1 hour after SAH. Starting 3 hours after SAH, collagen IV immunostaining was reduced or eliminated along segments of microvessels whereas MMP-9 staining was segmentally increased. These effects reached a maximum at 6 hours and returned toward those values in sham-operated controls at 48 hours.

Conclusions. Results of this study demonstrated an acute loss of collagen IV from the cerebral microvasculature after SAH and indicated that MMP-9 contributes to this event. The loss of collagen IV might contribute to the known failure of the blood—brain barrier after SAH.

Article Information

Address reprint requests to: Fatima A. Sehba, Ph.D., Department of Neurosurgery, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1136, New York, New York 10029–6574. email: fatima.sehba@mssm.edu.

© AANS, except where prohibited by US copyright law.

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Figures

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    Graphs demonstrating ICP and CBF after SAH. A significant elevation in ICP occurred on induction of SAH (A). Cerebral blood flow fell significantly on induction of SAH and recovered to less than 40% of the baseline value at 10 minutes after SAH (B). Data are represented as the means ± standard error of the mean. Asterisk indicates significant differences (p < 0.01) compared with time-matched sham-operated control animals.

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    Photomicrographs revealing collagen IV immunostaining in the rat striatum after SAH. Collagen IV staining is lost segmentally (arrows) after SAH, making blood vessels appear as interrupted sequences of segments rather than continuous profiles. The number of collagen IV—stained segments increased from 3 hours (A) to 6 hours (B), reflecting an active focal loss of collagen IV after SAH. Bar = 100 µm.

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    Bar graph depicting the number of blood vessels positive for collagen IV in basal (Bctx) and frontal cortex (Fctx), striatum (St), and hippocampus (Hi) of the right (Rt) hemisphere 3 hours after SAH (white bars) or sham surgery (black bars). After SAH, individual segments appeared to be divided into territories from which collagen was removed. No interhemispheric difference was found. Data are the means ± standard error of the mean per 4 × 105 µm2 microscopic field. Asterisk indicates a significant difference

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    In situ zymographs of rat striatum revealing microvascular collagenase activity at 3 (A), 6 (B), or 24 (C) hours after SAH. The images are gray-scale inverted to aid visualization. Fluorescent microvessels are visible at 3 and 6 hours, but largely absent at 24 hours after SAH. Bar = 100 µm.

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    Quantitative zymographic analysis. A: Graph demonstrating number of fluorescent microvessels in SAH-induced and sham-operated animals. Results of ANOVA showed a significant effect of time and treatment in both animal groups (see text). The number of fluorescent microvessels increased 3 hours after SAH, reached a maximum at 6 hours, and decreased to sham-operated values at 24 hours after SAH. B: Graph demonstrating values for SAH-induced animals expressed as ratios to sham-operated controls to eliminate the effect of nonspecific surgical trauma. All values are represented as the means ± standard error of the mean. Asterisk in panel A indicates a significant difference in a comparison between SAH-induced and sham-operated groups (p < 0.01). Double asterisks in panel B indicate that the 3- and 6-hour time points are significantly different from the other time points (p < 0.01).

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    Immunofluorescence images of collagen IV and MMP-9 immunoreactivity in the rat striatum 3 (A and B), 6 (C and D), or 48 (E and F) hours after SAH. Brain sections were viewed through rhodamine (collagen IV) and fluorescein (MMP-9) filters, and a single microscopic field was photographed with each filter separately. Images were superimposed to view microvessels positive for collagen IV only (thick arrows), MMP-9 only (arrowheads), or both collagen IV and MMP-9 (thin arrows). The length and number of microvascular segments stained with collagen IV only decreased, and the number of microvascular segments stained with MMP-9 only increased 3 to 6 hours after SAH. Microvascular segments stained with both collagen IV and MMP-9 were common at 3 (A and B) and 6 (C and D) hours after SAH, but were rare at 48 hours (E and F) after SAH. Microvascular segments stained with collagen IV appeared almost normal at 48 hours after SAH. Microvascular staining for MMP-9 decreased at 48 hours compared with that at 3 and 6 hours after SAH. Bar = 100 µm.

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    Graphs demonstrating quantitative immunofluorescence. The proportion of vessel segments positive for collagen IV (A) decreased up to 6 hours after SAH, whereas the proportion of segments stained for MMP-9 (B) increased. Both measures recovered by 48 hours post-SAH. These values represent the number of collagen IV/MMP-9 segments divided by the total number of immunostained segments in the same field. Parallel but much smaller changes in sham-operated animals were observed (note the magnitude of the line graphs). All values represent the means ± standard error of the mean accumulation across hemispheres and brain sections. Asterisks denote a significant difference (p < 0.01) between time-matched sham-operated animals.

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