Impaired Hippocampal Neurovascular Coupling in a Mouse Model of Alzheimer’s Disease

Alzheimer’s disease (AD), the most common form of dementia, is characterized by neuronal degeneration and cerebrovascular dysfunction. Increasing evidence indicates that cerebrovascular dysfunction may be a key or an aggravating pathogenic factor in AD. This emphasizes the importance to investigate the tight coupling between neuronal activity and cerebral blood flow (CBF) termed neurovascular coupling (NVC). NVC depends on all cell types of the neurovascular unit within which astrocytes are important players in the progression of AD. Hence, the objective of this study was to characterize the hippocampal NVC in a mouse model of AD. Hippocampal NVC was studied in 6-month-old amyloid-beta precursor protein (APP) transgenic mice and their corresponding wild-type littermates using in vivo laser Doppler flowmetry to measure CBF in area CA1 of the hippocampus in response to Schaffer collaterals stimulation. Ex vivo two-photon microscopy experiments were performed to determine astrocytic Ca2+ and vascular responses to electrical field stimulation (EFS) or caged Ca2+ photolysis in hippocampal slices. Neuronal synaptic transmission, astrocytic endfeet Ca2+ in correlation with reactive oxygen species (ROS), and vascular reactivity in the presence or absence of Tempol, a mimetic of superoxide dismutase, were further investigated using electrophysiological, caged Ca2+ photolysis or pharmacological approaches. Whisker stimulation evoked-CBF increases and ex vivo vascular responses to EFS were impaired in APP mice compared with their age-matched controls. APP mice were also characterized by decreased basal synaptic transmission, a shorter astrocytic Ca2+ increase, and altered vascular response to elevated perivascular K+. However, long-term potentiation, astrocytic Ca2+ amplitude in response to EFS, together with vascular responses to nitric oxide remained unchanged. Importantly, we found a significantly increased Ca2+ uncaging-induced ROS production in APP mice. Tempol prevented the vascular response impairment while normalizing astrocytic Ca2+ in APP mice. These findings suggest that NVC is altered at many levels in APP mice, at least in part through oxidative stress. This points out that therapies against AD should include an antioxidative component to protect the neurovascular unit.

Vascular Response after Directional Coronary Atherectomy for Left Main Bifurcation Lesion

Purpose: To evaluate the vascular response after directional coronary atherectomy (DCA) for left main (LM) bifurcation lesion.Methods: This study was a retrospective, single-center study enrolling 31 patients who underwent stent-less therapy using DCA followed by drug-coated balloon angioplasty for LM bifurcation lesion. We compared the intravascular ultrasound (IVUS) findings pre- and post DCA. Results: After DCA, the lumen and vessel areas significantly increased whereas the plaque area (PA) and %PA significantly decreased. When the lesions were divided into small and large vessel groups using the median vessel area value, the maximum balloon pressure of the DCA catheter was greater in the large than in the small vessel group. Changes in the lumen and vessel areas were also significantly greater in the large than in the small vessel group. Conversely, the PA and %PA changes were similar between the groups. Conclusion: The main vascular responses associated with lumen enlargement after DCA were plaque reduction and vessel expansion. Contribution of vessel expansion to lumen enlargement was larger than the effect of plaque reduction in large than in small-vessel lesions.

Localized Oxygen Exchange Platform for Intravital Video Microscopy Investigations of Microvascular Oxygen Regulation

Intravital microscopy has proven to be a powerful tool for studying microvascular physiology. In this study, we propose a gas exchange system compatible with intravital microscopy that can be used to impose gas perturbations to small localized regions in skeletal muscles or other tissues that can be imaged using conventional inverted microscopes. We demonstrated the effectiveness of this system by locally manipulating oxygen concentrations in rat extensor digitorum longus muscle and measuring the resulting vascular responses. A computational model of oxygen transport was used to partially validate the localization of oxygen changes in the tissue, and oxygen saturation of red blood cells flowing through capillaries were measured as a surrogate for local tissue oxygenation. Overall, we have demonstrated that this approach can be used to study dynamic and spatial responses to local oxygen challenges to the microenvironment of skeletal muscle.