Leptomeningeal collaterals regulate reperfusion in ischemic stroke and rescue the brain from futile recanalization.

Recanalization is the mainstay of ischemic stroke treatment. However, even with timely clot removal, many stroke patients recover poorly. Leptomeningeal collaterals (LMCs) are pial anastomotic vessels with yet-unknown functions. We applied laser speckle imaging, ultrafast ultrasound, and two-photon microscopy in a thrombin-based mouse model of stroke and fibrinolytic treatment to show that LMCs maintain cerebral autoregulation and allow for gradual reperfusion, resulting in small infarcts. In mice with poor LMCs, distal arterial segments collapse, and deleterious hyperemia causes hemorrhage and mortality after recanalization. In silico analyses confirm the relevance of LMCs for preserving perfusion in the ischemic region. Accordingly, in stroke patients with poor collaterals undergoing thrombectomy, rapid reperfusion resulted in hemorrhagic transformation and unfavorable recovery. Thus, we identify LMCs as key components regulating reperfusion and preventing futile recanalization after stroke. Future therapeutic interventions should aim to enhance collateral function, allowing for beneficial reperfusion after stroke.

The role of leptomeningeal collaterals in redistributing blood flow during stroke.

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.

Bidirectional astrocytic GLUT1 activation by elevated extracellular K.

The acute rise in interstitial K+ that accompanies neural activity couples the energy demand of neurons to the metabolism of astrocytes. The effects of elevated K+ on astrocytes include activation of aerobic glycolysis, inhibition of mitochondrial respiration and the release of lactate. Using a genetically encoded FRET glucose sensor and a novel protocol based on 3-O-methylglucose trans-acceleration and numerical simulation of glucose dynamics, we report that extracellular K+ is also a potent and reversible modulator of the astrocytic glucose transporter GLUT1. In cultured mouse astrocytes, the stimulatory effect developed within seconds, engaged both the influx and efflux modes of the transporter, and was detected even at 1 mM incremental K+ . The modulation of GLUT1 explains how astrocytes are able to maintain their glucose pool in the face of strong glycolysis stimulation. We propose that the stimulation of GLUT1 by K+ supports the production of lactate by astrocytes and the timely delivery of glucose to active neurons.

Predicting Vessel Diameter Changes to Up-Regulate Biphasic Blood Flow During Activation in Realistic Microvascular Networks.

A dense network of blood vessels distributes blood to different regions of the brain. To meet the temporarily and spatially varying energy demand resulting from changes in neuronal activity, the vasculature is able to locally up-regulate the blood supply. However, to which extent diameter changes of different vessel types contribute to the up-regulation, as well as the spatial and temporal characteristics of their changes, are currently unknown. Here, we present a new simulation method, which solves an inverse problem to calculate diameter changes of individual blood vessels needed to achieve predefined blood flow distributions in microvascular networks. This allows us to systematically compare the impact of different vessel types in various regulation scenarios. Moreover, the method offers the advantage that it handles the stochastic nature of blood flow originating from tracking the movement of individual red blood cells. Since the inverse problem is formulated for time-averaged pressures and flow rates, a deterministic approach for calculating the diameter changes is used, which allows us to apply the method for large realistic microvascular networks with high-dimensional parameter spaces. Our results obtained in both artificial and realistic microvascular networks reveal that diameter changes at the level of capillaries enable a very localized regulation of blood flow. In scenarios where only larger vessels, i.e., arterioles, are allowed to adapt, the flow increase cannot be confined to a specific activated region and flow changes spread into neighboring regions. Furthermore, relatively small dilations and constrictions of all vessel types can lead to substantial changes of capillary blood flow distributions. This suggests that small scale regulation is necessary to obtain a localized increase in blood flow.

Cost and speed of locomotion for rotifers.

The hypothesis that the ciliary locomotion of rotifers is size limited and that it accounts of a significant portion of the energy budget was investigated using the genera Brachionus and Asplanchna. Speed of movement was measured among clones of different size in Brachionus, which shows little size variation through development. The same tests were done among individuals of different size within a clone of Asplanchna, which shows significant postembryonic size increase. In both cases, relative speed (body lengths per second) decreased significantly as body size increased. On this basis, and ecologically limiting size for ciliary locomotion is proposed. The actual cost of locomotion was measured for Brachionus; it is 62% of total metabolism, even though the theoretical (calculated) power requirements are well below 1% of total metabolism. Ciliary locomotion in the Rotifera thus appears to be extremely inefficient (low ratio of theoretical to actual power requirements). This hypothesis is supported indirectly by the sensitivity of speed to total metabolic rate in Brachionus: both plateau over the temperature range 20-32°C and decline in parallel outside this range. Unexpectedly high actual cost of locomotion is proposed as an important disadvantage of the Rotifera, partly offsetting the advantages accruing to them from small body size.

Metabolic responses to temperature change in a tropical freshwater copepod (Mesocyclops brasilianus) and their adaptive significance.

Metabolic rates of Mesocyclops brasilianus from Lake Valencia, Venezuela, were determined at several temperatures spanning the environmental range (22-28° C). The QO2's (oxygen consumption per unit weight) of all Mesocyclops stages from Lake Valencia are higher than most but not all QO2's from temperate copepod species that have been studied. The QO2 is essentially static through naupliar development and shows a sudden jump between N6 and CI, which probably results from the major change in morphology and behavior at this point in the life history. QO2 declines steadily between CI and adult stages. Acclimated copepodite and adult Mesocyclops show a decreasing metabolic rate with increasing temperature (i.e. Q10< 1.0) over the temperature range 26-28° C. This is the range of temperatures normally encountered during the daily vertical migration when the lake is thermally stratified (April-November). Since vertical migration would result in a compromise between a fully acclimated and an acute response, a nearly constant metabolic rate or a slight decline in metabolic rate in the warmer water would be expected in field populations. The results thus show that the metabolic rate of Mesocyclops is not reduced when it moves into deeper (cooler) water, as would be predicted by certain energy-based hypotheses that have been used to explain vertical migration. In contrast to the low Q10's between 26 and 28° C, copepodites and adults have very high Q10 values in the range 22-26° C. This indicates an adaptive decrease in metabolic rate which is thermally programmed to coincide with the cooler temperatures that are encountered during the mixing season (December-March), when a drastic change in ecological conditions occurs in the lake.Nauplii show evidence of the same seasonal response but without the superimposed plateau at high temperatures, which they would not need because they are weak migrators. Nauplii show a plateau at the lowest temperatures, however, which suggests that a fixed metabolic reduction occurs at the onset of mixing and metabolism is not altered thereafter with declining temperature.The change in QO2 with temperature generally supports the hypothesis that all Mesocyclops stages are adapted to hold a high, constant metabolic rate through the diel cycle but experience a seasonal reduction in metabolic rate in response to major ecological changes in the lake at the time of seasonal mixing.