Ultra-Sensitive Molecular MRI of Vascular Cell Adhesion Molecule-1 Reveals a Dynamic Inflammatory Penumbra After Strokes

Abstract

Background and Purpose-Our aim was to assess the spatiotemporal evolution of the cerebrovascular inflammation occurring after ischemic and hemorrhagic strokes using a recently developed, fast, and ultra-sensitive molecular MRI method. Methods-We first assessed longitudinally the cerebrovascular inflammation triggered by collagenase-induced hemorrhage and by permanent/transient middle cerebral artery occlusion in mice, using MRI after injection of microparticles of iron oxide targeted to vascular cell adhesion molecule-1 (MPIOs-αVCAM-1). Thereafter, we used this method to study the anti-inflammatory effects of celecoxib, atorvastatin, and dipyridamole after stroke. Results-Using multiparametric MRI, we demonstrated that the level and the kinetics of cerebrovascular VCAM-1 expression depend on several parameters, including stroke pathogenesis, the natural history of the disease, and the administration of inflammation-modulating drugs. Interestingly, in transient middle cerebral artery occlusion and intracranial hemorrhage models, VCAM-1 expression was maximal at 24 hours and almost returned to baseline 5 days after stroke onset. In contrast, after permanent middle cerebral artery occlusion, VCAM-1 overexpression was sustained between 24 hours and 5 days, and was particularly significant in the peri-infarct areas. Our results suggest that these perilesional areas expressing VCAM-1 constitute an inflammatory penumbra that is recruited by the ischemic core during the subacute phase. Using MPIOs-αVCAM-1-enhanced imaging, we also provided evidence that celecoxib and atorvastatin (but not dipyridamole) alleviate VCAM-1 overexpression after stroke and prevent formation of the inflammatory penumbra. Conclusions-MPIOs-αVCAM-1-enhanced imaging seems to be promising in the detection of individuals presenting with severe cerebrovascular responses after stroke, which could therefore benefit from anti-inflammatory treatments.

Impact of Alcohol Consumption on the Outcome of Ischemic Stroke and Thrombolysis

“…Therefore, it is expected that tPA after intravenous injection mainly circulates not complexed to PAI-1 in both control and alcohol-treated mice. Thus, knowing that tPA clearance normally relies on LRP-1, 18 we also studied its expression levels in the liver, which interestingly, were dramatically decreased in alcohol-exposed mice. In parallel to reduced levels of hepatic LRP-1, we observed an increased bioavailability of exogenous, active tPA, with an impairment of tPA clearance by the liver: (1) exogenous tPA 555 remained longer in the blood of alcohol-exposed mice than in control mice and (2) in vivo 2-photon liver microscopy showed an inefficient passage of exogenous tPA 555 into the liver parenchyma after alcohol consumption.…”

“…This alteration of tPA clearance after alcohol consumption is correlated with a selective, tissue-specific reduction of the levels of hepatic low-density lipoprotein receptor-related protein 1 (LRP-1, receptor implicated in the clearance of tPA 17,18 ). Thus, we uncover here a critical role of the liverbrain axis in the beneficial effects of thrombolysis after stroke.…”

GpIbα-VWF blockade restores vessel patency by dissolving platelet aggregates formed under very high shear rate in mice

“…20,21 Cerebral blood flow (CBF) in the MCA territory was determined by laser Doppler flowmetry (Oxford Optronix). CBF was continuously measured before MCA occlusion (MCAo, 100% baseline) and throughout the duration of ischemia and thrombolysis.…”

“…1 Thus, in the range of physiological arterial shear rates (1000-10 000 s 21 ), large aggregate formation requires platelet activation and occurs in a GpIIb/IIIadependent manner. 8 Under very high shear rates (.10 000 s 21 ), platelet aggregation can occur independently of platelet activation.…”

Comparing Vessel Imaging

“…81 Advances in vascular MRI include improvements in visualization of vessel wall abnormalities, which may have a role in acute stroke investigation. Microparticles of iron oxide can detect inflammatory molecules (molecular MRI), 82 bright blood and black blood high-resolution MRI can evaluate vulnerable carotid 83,84 and intracranial plaque, 85 and thin-section multicontrast vessel wall MRI can examine different intracranial vascular pathologies. 86 Compressed sensing allows for dynamic (time resolved) contrast-enhanced MRA imaging that could include collateral filling.…”