An official website of the United States government
Autoregulation and neurovascular coupling are key mechanisms that modulate myogenic tone (MT) in vessels to regulate cerebral blood flow (CBF) during resting state and periods of increased neural activity, respectively. To determine relative contributions of distinct vascular zones across different cortical depths in CBF regulation, we developed a simplified yet detailed and computationally efficient model of the mouse cerebrovasculature. The model integrates multiple simplifications and generalizations regarding vascular morphology, the hierarchical organization of mural cells, and potentiation/inhibition of MT in vessels. Our analysis showed that autoregulation is the result of the synergy between these factors, but achieving an optimal balance across all cortical depths and throughout the autoregulation range is a complex task. This complexity explains the non-uniformity observed experimentally in capillary blood flow at different cortical depths. In silico simulations of cerebral autoregulation support the idea that the cerebral vasculature does not maintain a plateau of blood flow throughout the autoregulatory range and consists of both flat and sloped phases. We learned that small-diameter vessels with large contractility, such as penetrating arterioles and precapillary arterioles, have major control over intravascular pressure at the entry points of capillaries and play a significant role in CBF regulation. However, temporal alterations in capillary diameter contribute moderately to cerebral autoregulation and minimally to functional hyperemia. In addition, hemodynamic analysis shows that while hemodynamics within capillaries remain relatively stable across all cortical depths throughout the entire autoregulation range, significant variability in hemodynamics can be observed within the first few branch orders of precapillary arterioles or transitional zone vessels. The computationally efficient cerebrovasculature model, proposed in this study, provides a novel framework for analyzing dynamics of the CBF regulation where hemodynamic and vasodynamic interactions are the foundation on which more sophisticated models can be developed.
more »
« less
G Hartung, C Vesel, R Morley**, A Alaraj, J Sled, D Kleinfeld, A Linninger, Simulations of blood as a suspension predicts a depth dependent hematocrit in the circulation throughout the cerebral cortex, PLoS Computational Biology, 14(11), e1006549, 2018. (**REU participant)
Recent advances in modeling oxygen supply to cortical brain tissue have begun to elucidate the functional mechanisms of neurovascular coupling. While the principal mechanisms of blood flow regulation after neuronal firing are generally known, mechanistic hemodynamic simulations cannot yet pinpoint the exact spatial and temporal coordination between the network of arteries, arterioles, capillaries and veins for the entire brain. Because of the potential significance of blood flow and oxygen supply simulations for illuminating spatiotemporal regulation inside the cortical microanatomy, there is a need to create mathematical models of the entire cerebral circulation with realistic anatomical detail. Our hypothesis is that an anatomically accurate reconstruction of the cerebrocirculatory architecture will inform about possible regulatory mechanisms of the neurovascular interface. In this article, we introduce large-scale networks of the murine cerebral circulation spanning the Circle of Willis, main cerebral arteries connected to the pial network down to the microcirculation in the capillary bed. Several multiscale models were generated from state-of-the-art neuroimaging data. Using a vascular network construction algorithm, the entire circulation of the middle cerebral artery was synthesized. Blood flow simulations indicate a consistent trend of higher hematocrit in deeper cortical layers, while surface layers with shorter vascular path lengths seem to carry comparatively lower red blood cell (RBC) concentrations. Moreover, the variability of RBC flux decreases with cortical depth. These results support the notion that plasma skimming serves a self-regulating function for maintaining uniform oxygen perfusion to neurons irrespective of their location in the blood supply hierarchy. Our computations also demonstrate the practicality of simulating blood flow for large portions of the mouse brain with existing computer resources. The efficient simulation of blood flow throughout the entire middle cerebral artery (MCA) territory is a promising milestone towards the final aim of predicting blood flow patterns for the entire brain.
more »
« less
- Award ID(s):
- 1706921
- PAR ID:
- 10099205
- Date Published:
- Journal Name:
- PLOS computational biology
- Volume:
- 14
- Issue:
- 11
- ISSN:
- 1553-7358
- Page Range / eLocation ID:
- 1-25
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Abstract Studying brain‐wide hemodynamic responses to different stimuli at high spatiotemporal resolutions can help gain new insights into the mechanisms of neuro‐ diseases and ‐disorders. Nonetheless, this task is challenging, primarily due to the complexity of neurovascular coupling, which encompasses interdependent hemodynamic parameters including cerebral blood volume (CBV), cerebral blood flow (CBF), and cerebral oxygen saturation (SO2). The current brain imaging technologies exhibit inherent limitations in resolution, sensitivity, and imaging depth, restricting their capacity to comprehensively capture the intricacies of cerebral functions. To address this, a multimodal functional ultrasound and photoacoustic (fUSPA) imaging platform is reported, which integrates ultrafast ultrasound and multispectral photoacoustic imaging methods in a compact head‐mountable device, to quantitatively map individual dynamics of CBV, CBF, and SO2as well as contrast agent enhanced brain imaging at high spatiotemporal resolutions. Following systematic characterization, the fUSPA system is applied to study brain‐wide cerebrovascular reactivity (CVR) at single‐vessel resolution via relative changes in CBV, CBF, and SO2in response to hypercapnia stimulation. These results show that cortical veins and arteries exhibit differences in CVR in the stimulated state and consistent anti‐correlation in CBV oscillations during the resting state, demonstrating the multiparametric fUSPA system's unique capabilities in investigating complex mechanisms of brain functions.more » « less
-
Abstract ObjectiveAn improved understanding of the role of the leptomeningeal collateral circulation in blood flow compensation following middle cerebral artery (MCA) occlusion can contribute to more effective treatment development for ischemic stroke. The present study introduces a model of the cerebral circulation to predict cerebral blood flow and tissue oxygenation following MCA occlusion. MethodsThe model incorporates flow regulation mechanisms based on changes in pressure, shear stress, and metabolic demand. Oxygen saturation in cerebral vessels and tissue is calculated using a Krogh cylinder model. The model is used to assess the effects of changes in oxygen demand and arterial pressure on cerebral blood flow and oxygenation after MCA occlusion. ResultsAn increase from five to 11 leptomeningeal collateral vessels was shown to increase the oxygen saturation in the region distal to the occlusion by nearly 100%. Post‐occlusion, the model also predicted a loss of autoregulation and a decrease in flow to the ischemic territory as oxygen demand was increased; these results were consistent with data from experiments that induced cerebral ischemia. ConclusionsThis study highlights the importance of leptomeningeal collaterals following MCA occlusion and reinforces the idea that lower oxygen demand and higher arterial pressure improve conditions of flow and oxygenation.more » « less
-
Atherosclerosis and vascular disease of larger arteries are often associated with hypoxia within the layers of the vascular wall. In this review, we begin with a brief overview of the molecular changes in vascular cells associated with hypoxia and then emphasize the transport mechanisms that bring oxygen to cells within the vascular wall. We focus on fluid mechanical factors that control oxygen transport from lumenal blood flow to the intima and inner media layers of the artery, and solid mechanical factors that influence oxygen transport to the adventitia and outer media via the wall's microvascular system—the vasa vasorum (VV). Many cardiovascular risk factors are associated with VV compression that reduces VV perfusion and oxygenation. Dysfunctional VV neovascularization in response to hypoxia contributes to plaque inflammation and growth. Disturbed blood flow in vascular bifurcations and curvatures leads to reduced oxygen transport from blood to the inner layers of the wall and contributes to the development of atherosclerotic plaques in these regions. Recent studies have shown that hypoxia-inducible factor-1α (HIF-1α), a critical transcription factor associated with hypoxia, is also activated in disturbed flow by a mechanism that is independent of hypoxia. A final section of the review emphasizes hypoxia in vascular stenting that is used to enlarge vessels occluded by plaques. Stenting can compress the VV leading to hypoxia and associated intimal hyperplasia. To enhance oxygen transport during stenting, new stent designs with helical centrelines have been developed to increase blood phase oxygen transport rates and reduce intimal hyperplasia. Further study of the mechanisms controlling hypoxia in the artery wall may contribute to the development of therapeutic strategies for vascular diseases.more » « less
-
Traumatic brain injury poses a major public health challenge with significant immediate and long-term effects. Repetitive head trauma is an ongoing area of research, and little is known about the response of cerebral blood vessels to such loading. This study investigated the mechanical response of cerebral arteries to repetitive overstretch, hypothesizing that repeated overstretch leads to cumulative damage. To test this hypothesis, middle cerebral artery segments from twelve piglets were subjected to sub-yield, high-rate overstretch of varying severities, with up to 10 repetitions. The stress-stretch behavior of the vessels revealed that repetitive overstretch caused progressive softening that increased with both overstretch magnitude and number of exposures. This softening was notably limited to the toe region, with no changes occurring in the higher-stress, linear portion of the repeated overstretch curves. Mild-to-moderate overstretches resulted in gradual softening, while severe overstretches caused dramatic softening with the first exposure and little further change with subsequent overstretches. Mildly damaged vessels displayed a small amount of recovery with time, but the magnitude of this recovery was minimal and declined with increasing repetitions and severity. No clear relationship was observed between collagen denaturation and the magnitude and number of overstretches. These findings provide important insights into the mechanics of cerebral vessels under repetitive loading, suggesting that vascular damage from repeated trauma accumulates, potentially exacerbating existing injury. These results increase understanding of soft tissue damage and inform the development of constitutive damage models for cerebral arteries, a critical tool needed to improve predictions of traumatic brain injury progression. STATEMENT OF SIGNIFICANCE: This study investigates the mechanical response of cerebral arteries to repetitive overstretch, revealing cumulative softening effects. Unlike previous studies focusing on single overstretch events, our research is the first to explore repetitive exposures in cerebral arteries and to report softening as a function of both overstretch magnitude and number of exposures. Given the role of cerebral vessels in maintaining a healthy brain and their contributions to the structural response of the brain in TBI events, progressive vessel softening in repetitive TBI may lead to increased vulnerability with the potential to exacerbate existing injury. These findings enhance understanding of soft tissue damage mechanisms, providing critical insights for developing constitutive damage models and improving injury predictions in repeated TBI.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/1006549
