Rapamycin Increases Collateral Circulation in Rodent Brain after Focal Ischemia as detected by Multiple Modality Dynamic Imaging

Rationale: Brain collaterals contribute to improving ischemic stroke outcomes. However, dynamic and timely investigations of collateral blood flow and collateral restoration in whole brains of living animals have rarely been reported. Methods: Using multiple modalities of imaging, including synchrotron radiation angiography, laser speckle imaging, and micro-CT imaging, we dynamically explored collateral circulation throughout the whole brain in the rodent middle cerebral artery occlusion model. Results: We demonstrated that compared to control animals, 4 neocollaterals gradually formed between the intra- and extra-arteries in the skull base of model animals after occlusion (p<0.05). Two main collaterals were critical to the supply of blood from the posterior to the middle cerebral artery territory in the deep brain (p<0.05). Abundant small vessel and capillary anastomoses were detected on the surface of the cortex between the posterior and middle cerebral artery and between the anterior and middle cerebral artery (p<0.05). Collateral perfusion occurred immediately (≈15 min) and was maintained for up to 14 days after occlusion. Further study revealed that administration of rapamycin at 15 min after MCAO dilated the existing collateral vessels and promoted collateral perfusion. Principal conclusions: Our results provide evidence of collateral functional perfusion in the skull base, deep brain, and surface of the cortex. Rapamycin was capable of enlarging the diameter of collaterals, potentially extending the time window for ischemic stroke therapy.