VEGF signaling regulates the fate of obstructed capillaries in mouse cortex

Reeson, Patrick; Choi, Kevin J.; Brown, Craig E.

doi:10.7554/elife.33670

Cited by 68 publications

(154 citation statements)

References 60 publications

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“…The vast majority of capillaries showed continuous flow throughout, although a small fraction did show brief stoppages lasting several seconds (Fig. 3A), consistent with previous work (41, 42). These ‘stalls’ were infrequent prior to injury, but increased dramatically in both number and duration after mild TBI.…”

Section: Resultssupporting

confidence: 91%

“…Disorders such as Alzheimer’s disease and stroke (54) can lead to structural remodeling of the vascular tree that chronically impairs neuronal blood supply (54). Prolonged capillary blockages occur even in healthy tissue, and are linked to subsequent pruning of the stalled segments (41, 42), raising the possibility that the extended stalls we observed could drive similar remodeling of the cortical vasculature.…”

Section: Resultsmentioning

confidence: 89%

“…CBF decreases may also arise at the level of capillaries, whose tight size tolerances may make them particularly sensitive to occlusion during periods of reduced supply from upstream vessels. Capillary stalls occur at low levels even under normal conditions (41, 42), and may be increased by pathological constriction of their surrounding pericytes as seen in stroke and hypoxia (104–106). Inflammatory responses to injury may also increase the “stickiness” of capillary walls, leading to leukocyte and platelet adhesion (17, 47, 107, 108).…”

Section: Discussionmentioning

confidence: 99%

“…The number and duration of capillary stalls were manually identified from angiogram images using custom MATLAB code. Temporarily stalled segments were defined as those alternating between present and absent (i.e., loss of flow signal in >50% of their length) in each ~8.5 minute angiogram time series following previously established protocols (41, 42). Continuously stalled segments were missing during one or more entire time series but reappeared at a later time point.…”

Section: Methodsmentioning

confidence: 99%

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Rapid disruption of the cortical microcirculation after mild traumatic brain injury

Witkowski¹,

Erdener²,

Kılıç³

et al. 2019

Preprint

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Keywords: traumatic brain injury, mouse, weight drop injury, cerebral blood flow, capillary, in 21 vivo, laser speckle contrast imaging, optical coherence tomography, two-photon imaging 22 23 24 Acknowledgments: We thank Tim Otchy, Jennifer Morgan, and members of the Davison and 25 Boas laboratories for comments and discussion. This work was supported by Boston University 26 startup funds.Abstract 30 Traumatic brain injury (TBI) is a major source of cognitive deficits affecting millions annually. The 31 bulk of human injuries are mild, causing little or no macroscopic damage to neural tissue, yet can 32 still lead to long-term neuropathology manifesting months or years later. Although the cellular 33 stressors that ultimately lead to chronic pathology are poorly defined, one notable candidate is 34 metabolic stress due to reduced cerebral blood flow (CBF), which is common to many forms of 35 TBI. Here we used high-resolution in vivo intracranial imaging in a rodent injury model to 36 characterize deficits in the cortical microcirculation during both acute and chronic phases after 37 mild TBI. We found that CBF dropped precipitously during immediate post-injury periods, 38 decreasing to less than half of baseline levels within minutes and remaining suppressed for 1.5-39 2 hours. Repeated time-lapse imaging of the cortical microvasculature revealed further striking 40 flow deficits in the capillary network, where 18% of vessels were completely occluded for 41 extended periods after injury, and an additional >50% showed substantial stoppages. Decreased 42 CBF was paralleled by extensive vasoconstriction that is likely to contribute to loss of flow. Our 43 data indicate a major role for vascular dysfunction in even mild forms of TBI, and suggest that 44 acute post-injury periods may be key therapeutic windows for interventions that restore flow 45 and mitigate metabolic stress. 46 47 88 dysfunction across the cortical microvasculature, where a large fraction of individual capillaries 89were occluded for periods of minutes or longer, leading to localized regions with complete loss 90 5 of perfusion. CBF largely returned to normal by 3 hours after injury and showed no measurable 91 deficits when tracked until 3 weeks. Reduced CBF was paralleled by pronounced 92 vasoconstriction, identifying a potential mechanism contributing to disrupted flow. This rapid 93 and extensive vascular dysfunction highlights the importance of immediate post-injury periods 94 for delivering interventions, and suggests that relieving vasoconstriction will be a promising 95 avenue for countering the effects of mild injury. 96 97 Methods 98 99 Animals and surgical procedures 100 All experiments were performed in 2-5 month-old male and female C57BL6/J mice in accordance 101 with guidelines of the Boston University Institutional Animal Care and Use Committee. Animals 102 were group housed on a 12-hour light/dark cycle with ad libitum access to food and water. 103 Chronic cranial windows were implanted using standard procedures (30, 31). Brie...

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Rapid disruption of the cortical microcirculation after mild traumatic brain injury

Witkowski¹,

Erdener²,

Kılıç³

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…String vessels are known to emerge during the course of vascular regression, which is tightly regulated during angiogenesis and neovascularization [30,38,51]. Development of string vessels can be also mediated by a loss of factors that promote endothelial cell survival and angiogenesis such as vascular endothelial growth factor (VEGF) [3,10,40]. In our cases, Coll4-positive string vessels at microinfarcts and their periphery lacked UEA-l expression indicating endothelial recession, which is associated with cessation of blood perfusion in the vessels affected [10,22,55].…”

Section: Discussionmentioning

confidence: 99%

Histological correlates of postmortem ultra-high-resolution single-section MRI in cortical cerebral microinfarcts

Yilmazer-Hanke

Mayer

Müller³

et al. 2020

acta neuropathol commun

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The identification of cerebral microinfarctions with magnetic resonance imaging (MRI) and histological methods remains challenging in aging and dementia. Here, we matched pathological changes in the microvasculature of cortical cerebral microinfarcts to MRI signals using single 100 μm-thick histological sections scanned with ultra-highresolution 11.7 T MRI. Histologically, microinfarcts were located in superficial or deep cortical layers or transcortically, compatible with the pattern of layer-specific arteriolar blood supply of the cerebral cortex. Contrary to acute microinfarcts, at chronic stages the core region of microinfarcts showed pallor with extracellular accumulation of lipofuscin and depletion of neurons, a dense meshwork of collagen 4-positive microvessels with numerous string vessels, CD68-positive macrophages and glial fibrillary acidic protein (GFAP)-positive astrocytes. In MRI scans, cortical microinfarcts at chronic stages, called chronic cortical microinfarcts here, gave hypointense signals in T1-weighted and hyperintense signals in T2-weighted images when thinning of the tissue and cavitation and/or prominent iron accumulation were present. Iron accumulation in chronic microinfarcts, histologically verified with Prussian blue staining, also produced strong hypointense T2*-weighted signals. In summary, the microinfarct core was occupied by a dense microvascular meshwork with string vessels, which was invaded by macrophages and astroglia and contained various degrees of iron accumulation. While postmortem ultra-high-resolution single-section imaging improved MRI-histological matching and the structural characterization of chronic cortical cerebral microinfarcts, miniscule microinfarcts without thinning or iron accumulation could not be detected with certainty in the MRI scans. Moreover, string vessels at the infarct margin indicate disturbances in the microcirculation in and around microinfarcts, which might be exploitable in the diagnostics of cortical cerebral microinfarcts with MRI in vivo.

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Computational models for generating microvascular structures: Investigations beyond medical imaging resolution

Apeldoorn

Safaei

Paton

et al. 2022

WIREs Mechanisms of Disease

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Angiogenesis, arteriogenesis, and pruning are revascularization processes essential to our natural vascular development and adaptation, as well as central players in the onset and development of pathologies such as tumoral growth and stroke recovery. Computational modeling allows for repeatable experimentation and exploration of these complex biological processes. In this review, we provide an introduction to the biological understanding of the vascular adaptation processes of sprouting angiogenesis, intussusceptive angiogenesis, anastomosis, pruning, and arteriogenesis, discussing some of the more significant contributions made to the computational modeling of these processes. Each computational model represents a theoretical framework for how biology functions, and with rises in computing power and study of the problem these frameworks become more accurate and complete. We highlight physiological, pathological, and technological applications that can be benefit from the advances performed by these models, and we also identify which elements of the biology are underexplored in the current state‐of‐the‐art computational models. This article is categorized under: Cancer > Computational Models Cardiovascular Diseases > Computational Models

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VEGF signaling regulates the fate of obstructed capillaries in mouse cortex

Cited by 68 publications

References 60 publications

Rapid disruption of the cortical microcirculation after mild traumatic brain injury

Rapid disruption of the cortical microcirculation after mild traumatic brain injury

Histological correlates of postmortem ultra-high-resolution single-section MRI in cortical cerebral microinfarcts

Computational models for generating microvascular structures: Investigations beyond medical imaging resolution

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