Stroke induces angiogenesis in the peri-infarct region. It is not known whether angiogenesis occurs in the subventricular zone (SVZ) of the lateral ventricle after stroke. The SVZ is a neural stem cell niche containing vascular plexus that supports adult neurogenesis. We characterized longitudinal changes of vascular structures in the SVZ niche after stroke using whole mounts, an organotypic preparation of the SVZ in which the 3D cell-vessel relationships are preserved.
Adult mice were subjected to middle cerebral artery occlusion (MCAO). The vascular architectures within the 50 μm thick SVZ of immunostained whole mounts were imaged by 3D confocal microscopy. In non-MCAO mice (n=4), 2±0.2% of endothelial cells were proliferative (BrdU+/CD31+). Blood vessels in this niche constituted 2.6±0.01% of the total volume with 75±17 vascular branches. However, 7 and 14 days after MCAO, proliferated endothelial cells significantly (p<0.05) increased to 12±1% (n=5) and 15±1 % (n=5), respectively, which was followed by substantial increases in vascular volume at 14 (4.2±0.01%, n=3), 30 (4.9±0.05%, n=3), and 90 (5.7±0.01%, n=3) days, but not at 7 days after MCAO. Moreover, vascular branches increased significantly to 156±27 and 216±8 at 30 and 90 days, respectively, but not at 14 days. Interestingly, we detected increases in the number of string-like vessels starting at 14 days (731±79/mm
3
vs 476±41/mm
3
in control) which increased and persisted at 30 (1,824±255/mm
3
) and 90 (1,748±204/mm
3
) days after MCAO. These string-like vessels were not perfused by plasma. String vessels increase during embryonic angiogenesis. Collectively, these data indicate that stroke induces angiogenesis in the SVZ, which lasts at least 90 days after stroke. Moreover, stroke significantly increased neural stem cells (BrdU
+
/GFAP
+
, 13±3%, 15±3%, and 11±4% at 7, 14, and 90 days, respectively, vs 6±1% in control) and newborn neurons (BrdU
+
/DCX
+
, 14±2% and 12±2.0% at 7 and 14 days, respectively, vs 4±1% in control). Neural stem cells at the ventricular surface extended their processes to the blood vessels in the SVZ.
Our data indicate that stroke induces angiogenesis in the SVZ, which is associated with stroke-induced neurogenesis.
The sphingosine-1-phosphate analogue, FTY-720, promotes the proliferation of embryonic neural stem cells, enhances hippocampal neurogenesis and learning and memory abilities in adult mice
