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Deterioration of brain capillary flow and architecture is a hallmark of aging and dementia. It remains unclear how loss of brain pericytes in these conditions contributes to capillary dysfunction. Here, we conduct cause-and-effect studies by optically ablating pericytes in adult and aged mice in vivo. Focal pericyte loss induces capillary dilation without blood-brain barrier disruption. These abnormal dilations are exacerbated in the aged brain, and result in increased flow heterogeneity in capillary networks. A subset of affected capillaries experience reduced perfusion due to flow steal. Some capillaries stall in flow and regress, leading to loss of capillary connectivity. Remodeling of neighboring pericytes restores endothelial coverage and vascular tone within days. Pericyte remodeling is slower in the aged brain, resulting in regions of persistent capillary dilation. These findings link pericyte loss to disruption of capillary flow and structure. They also identify pericyte remodeling as a therapeutic target to preserve capillary flow dynamics. Using in vivo two-photon imaging, Berthiaume et al. demonstrate how pericyte loss during aging could contribute to deterioration of cerebral blood flow. They also show how pericyte remodeling reduces the deleterious effects of pericyte loss.

A better knowledge of the flow and pressure distribution in realistic microvascular networks is needed for improving our understanding of neurovascular coupling mechanisms and the related measurement techniques. Here, numerical simulations with discrete tracking of red blood cells (RBCs) are performed in three realistic microvascular networks from the mouse cerebral cortex. Our analysis is based on trajectories of individual RBCs and focuses on layer-specific flow phenomena until a cortical depth of 1 mm. The individual RBC trajectories reveal that in the capillary bed RBCs preferentially move in plane. Hence, the capillary flow field shows laminar patterns and a layer-specific analysis is valid. We demonstrate that for RBCs entering the capillary bed close to the cortical surface (< 400 μm) the largest pressure drop takes place in the capillaries (37%), while for deeper regions arterioles are responsible for 61% of the total pressure drop. Further flow characteristics, such as capillary transit time or RBC velocity, also vary significantly over cortical depth. Comparison of purely topological characteristics with flow-based ones shows that a combined interpretation of topology and flow is indispensable. Our results provide evidence that it is crucial to consider layer-specific differences for all investigations related to the flow and pressure distribution in the cortical vasculature. These findings support the hypothesis that for an efficient oxygen up-regulation at least two regulation mechanisms must be playing hand in hand, namely cerebral blood flow increase and microvascular flow homogenization. However, the contribution of both regulation mechanisms to oxygen up-regulation likely varies over depth.

Cortical microinfarcts are linked to pathologies like cerebral amyloid angiopathy and dementia. Despite their relevance for disease progression, microinfarcts often remain undetected and the smallest scale of blood flow disturbance has not yet been identified. We employed blood flow simulations in realistic microvascular networks from the mouse cortex to quantify the impact of single-capillary occlusions. Our simulations reveal that the severity of a microstroke is strongly affected by the local vascular topology and the baseline flow rate in the occluded capillary. The largest changes in perfusion are observed in capillaries with two inflows and two outflows. This specific topological configuration only occurs with a frequency of 8%. The majority of capillaries have one inflow and one outflow and is likely designed to efficiently supply oxygen and nutrients. Taken together, microstrokes bear potential to induce a cascade of local disturbances in the surrounding tissue, which might accumulate and impair energy supply locally. A blockage in one of the tiny blood vessels or capillaries of the brain causes a ‘microstroke’. Microstrokes do not cause the same level of damage as a major stroke, which is caused by a blockage in a larger blood vessel that completely cuts off oxygen to a part of the brain for a period. But microstrokes do increase the risk of developing conditions like dementia – including Alzheimer’s disease – later in life. People with these neurodegenerative conditions have fewer capillaries in their brains. The capillaries make up a mesh-like network of millions of vessels that supply most of the energy and oxygen to the brain. Repeated microstrokes may contribute to progressive loss of capillaries over time. Reduced numbers of capillaries may increase memory loss and other brain difficulties. To better understand how microstrokes affect blood flow in the brain, Schmid et al. created a computer model to simulate blood flow in capillaries in the mouse brain. Then, they modeled what happens to the blood flow when one capillary is blocked. The experiments showed that the configuration of the blocked capillary determines how much blood flow in neighboring capillaries changes. Blockages in capillaries with two vessels feeding in and two vessels feeding out caused the greatest blood flow disturbances. But these 2-in-2-out vessels only make up about 8% of all brain capillaries. Blockages in capillaries with different configurations with respect to feeding vessels had less effect. The experiments suggest that most microstrokes have limited effects on blood flow on the scale of the entire brain because of redundancies in the capillary network in the brain. However, the ability of the capillary network to adapt and reroute blood flow in response to small blockages may decrease with aging. Over time, ministrokes in a single capillary may set off a chain reaction of disturbed blood flow and more blockages. This may decrease energy and oxygen supplies explaining age- and disease-related brain decline. Better understanding the effects of microstrokes on blood flow may help scientists develop new ways to prevent such declines.

Capillaries are the prime location for oxygen and nutrient exchange in all tissues. Despite their fundamental role, our knowledge of perfusion and flow regulation in cortical capillary beds is still limited. Here, we use in vivo measurements and blood flow simulations in anatomically accurate microvascular network to investigate the impact of red blood cells (RBCs) on microvascular flow. Based on these in vivo and in silico experiments, we show that the impact of RBCs leads to a bias toward equating the values of the outflow velocities at divergent capillary bifurcations, for which we coin the term \"well-balanced bifurcations\". Our simulation results further reveal that hematocrit heterogeneity is directly caused by the RBC dynamics, i.e. by their unequal partitioning at bifurcations and their effect on vessel resistance. These results provide the first in vivo evidence of the impact of RBC dynamics on the flow field in the cortical microvasculature. By structural and functional analyses of our blood flow simulations we show that capillary diameter changes locally alter flow and RBC distribution. A dilation of 10% along a vessel length of 100 μm increases the flow on average by 21% in the dilated vessel downstream a well-balanced bifurcation. The number of RBCs rises on average by 27%. Importantly, RBC up-regulation proves to be more effective the more balanced the outflow velocities at the upstream bifurcation are. Taken together, we conclude that diameter changes at capillary level bear potential to locally change the flow field and the RBC distribution. Moreover, our results suggest that the balancing of outflow velocities contributes to the robustness of perfusion. Based on our in silico results, we anticipate that the bi-phasic nature of blood and small-scale regulations are essential for a well-adjusted oxygen and energy substrate supply.

Leptomeningeal collaterals (LMCs) connect the main cerebral arteries and provide alternative pathways for blood flow during ischaemic stroke. This is beneficial for reducing infarct size and reperfusion success after treatment. However, a better understanding of how LMCs affect blood flow distribution is indispensable to improve therapeutic strategies. Here, we present a novel in silico approach that incorporates case-specific in vivo data into a computational model to simulate blood flow in large semi-realistic microvascular networks from two different mouse strains, characterised by having many and almost no LMCs between middle and anterior cerebral artery (MCA, ACA) territories. This framework is unique because our simulations are directly aligned with in vivo data. Moreover, it allows us to analyse perfusion characteristics quantitatively across all vessel types and for networks with no, few and many LMCs. We show that the occlusion of the MCA directly caused a redistribution of blood that was characterised by increased flow in LMCs. Interestingly, the improved perfusion of MCA-sided microvessels after dilating LMCs came at the cost of a reduced blood supply in other brain areas. This effect was enhanced in regions close to the watershed line and when the number of LMCs was increased. Additional dilations of surface and penetrating arteries after stroke improved perfusion across the entire vasculature and partially recovered flow in the obstructed region, especially in networks with many LMCs, which further underlines the role of LMCs during stroke.

An amazingly wide range of complex behavior emerges from the cerebral cortex. Much of the information processing that leads to these behaviors is performed in neocortical circuits that span throughout the six layers of the cortex. Maintaining this circuit activity requires substantial quantities of oxygen and energy substrates, which are delivered by the complex yet well-organized and tightly-regulated vascular system. In this review, we provide a detailed characterization of the most relevant anatomical and functional features of the cortical vasculature. This includes a compilation of the available data on laminar variation of vascular density and the topological aspects of the microvascular system. We also review the spatio-temporal dynamics of cortical blood flow regulation and oxygenation, many aspects of which remain poorly understood. Finally, we discuss some of the important implications of vascular density, distribution, oxygenation and blood flow regulation for (laminar) fMRI. •We review the architecture and functionality of the cortical microvasculature.•We summarize topological characteristics of pial, penetrating and micro-vessels.•We compare vascular density over the cortical depth for different species.•We summarize the vascular and oxygenation response to neuronal activation.•We discuss the relevance of these factors for laminar fMRI.

Cerebral autoregulation stabilizes cerebral blood flow (CBF) in response to variations in blood pressure, primarily through dynamic adjustments in arterial caliber. However, the impact of autoregulation mechanisms on local vascular responses and microcirculatory perfusion remains poorly understood. Given that impaired autoregulation is common in pathologies such as ischemic stroke, quantifying vessel-level responses can help to inform clinical strategies. Here, we present a novel in silico model that incorporates static myogenic and endothelial regulatory mechanisms to simulate CBF in large microvascular networks derived from realistic surface vasculatures of mice with and without leptomeningeal collaterals (LMCs). We assessed the role of autoregulation mechanisms under three conditions: i) healthy autoregulation, ii) ischaemic stroke and reperfusion with altered vascular reactivity, and iii) chronic autoregulation dysfunction after stroke. For healthy autoregulation, our model reproduced the classic static autoregulation curve and identified the dominant contribution of surface arteries in buffering pressure changes. Networks with lower descending arteriole density exhibited more extensive arterial dilations, reflecting the topological influence on vessel diameter changes. During reperfusion after stroke, we investigated the interplay between LMCs and parameters governing the vasoreactive response. While LMCs play a crucial role in maintaining residual perfusion in adjacent regions during MCA occlusion, our results suggest that their extent alone does not substantially influence perfusion after recanalization. Instead, alterations in myogenic reactivity emerged as the key contributor to hyperperfusion, underscoring the importance of regulatory mechanisms in determining reperfusion outcomes. To mimic chronic autoregulatory dysfunction, we progressively impaired regulatory capacity in arteries on the middle cerebral artery (MCA) side, reflecting the territory previously affected by stroke. The loss of autoregulation in proximal vessels significantly disrupts capillary perfusion and alters the autoregulation curve. To our knowledge, this is the first in silico study to explore cerebral autoregulation at the microvascular level under both physiological and pathological conditions. Our findings provide mechanistic insight into how individual vessel behavior shapes global flow regulation and highlight myogenic tone as a potential therapeutic target to reduce reperfusion-related complications in stroke.

The progressive loss of cerebral white matter during aging contributes to cognitive decline, but whether reduced blood flow is a cause or consequence remains debated. Using deep multi-photon imaging in mice, we examined microvascular networks perfusing myelinated tissues in cortical layer 6 and corpus callosum. We identified sparse, wide-reaching venules, termed principal cortical venules, that exclusively drain deep tissues and resemble vasculature at the human cortex and U-fiber interface. Aging involved selective constriction and rarefaction of capillaries in deep branches of principal cortical venules. This resulted in mild hypoperfusion that was associated with microgliosis, astrogliosis and demyelination in deep tissues, but not upper cortex. Inducing a comparable hypoperfusion in adult mice using carotid artery stenosis triggered a similar tissue pathology specific to layer 6 and corpus callosum. Thus, impaired capillary-venous drainage is a contributor to hypoperfusion and a potential therapeutic target for preserving blood flow to white matter during aging.

The myogenic response is the key autoregulatory mechanism setting cerebral blood flow and its mechanistic foundation is intimately tied to depolarization and the voltage gating of L-type Ca2+ channels (CaV1.2). While critical, this study argues for an additional mechanism, that of pressure itself enhancing CaV1.2 activity via cooperative gating and perimembrane trafficking of channel's subunits. These novel insights were pursued at the cell level using patch-clamp electrophysiology and advanced microscopy, and then functionally in pressurized arteries through measures of tone and intracellular [Ca2+]i. Key findings were confirmed in mutant mice with disrupted functional coupling and translated into arteries procured from human brain tissue. From cerebral blood flow simulations of semi-realistic microvascular networks, we predict that loss of this alternative mechanism leads to maldistribution of brain blood flow and potentially a diminishment of cognitive function. This study reveals previously unrecognized pressure-sensitive CaV1.2 regulatory mechanism that advances understanding of cerebral blood flow.Competing Interest StatementThe authors have declared no competing interest.Footnotes* https://github.com/mccsssk2/Mironova_et_al_20242025\\* https://github.com/Franculino/microBlooMFunder Information DeclaredCanadian Institutes of Health Research, RN452347 - 462379Swiss National Science Foundation, 200703, 202199Hartmann Muller Foundation, 2885