Aerobic exercise reverses aging-induced depth-dependent decline in cerebral microcirculation

Shin, Paul; Pian, Qi; Ishikawa, Hidehiro; Hamanaka, Gen; Mandeville, Emiri T.; Guo, Shuzhen; Fu, Binying; Alfadhel, Mohammed; Allu, Srinivasa Rao; Şencan, İkbal; Li, Baoqiang; Ran, Chongzhao; Vinogradov, Sergei A.; Ayata, Cenk; Lo, Eng H.; Arai, Ken; Devor, Anna; Sakadžić, Sava

doi:10.1101/2023.02.12.528244

Cited by 3 publications

(6 citation statements)

References 67 publications

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“…This gradation was dampened in aged mice because of reduced flow in deep tissues and increased flow in upper cortex. These findings align with previous reports of both increases 39 and decreases 40 in blood flow with brain aging, and explain how these conditions co-exist, but at different cortical depths. Our observation of age-related capillary dilation in upper cortex is also consistent with prior work.…”

Section: Discussionsupporting

confidence: 92%

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Impaired drainage through capillary-venous networks contributes to age-related white matter loss

Stamenkovic,

Schmid,

Weitermann

et al. 2024

Preprint

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The gradual loss of cerebral white matter contributes to cognitive decline during aging. However, microvascular networks that support the metabolic demands of white matter remain poorly defined. We used in vivo deep multi-photon imaging to characterize microvascular networks that perfuse cortical layer 6 and corpus callosum, a highly studied region of white matter in the mouse brain. We show that these deep tissues are exclusively drained by sparse and wide-reaching venules, termed principal cortical venules, which mirror vascular architecture at the human cortical-U fiber interface. During aging, capillary networks draining into deep branches of principal cortical venules are selectively constricted, reduced in density, and diminished in pericyte numbers. This causes hypo-perfusion in deep tissues, and correlates with gliosis and demyelination, whereas superficial tissues become relatively hyper-perfused. Thus, age-related impairment of capillary-venular drainage is a key vascular deficit that contributes to the unique vulnerability of cerebral white matter during brain aging.

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Section: Discussionsupporting

confidence: 92%

“…24,49 Similarly, life-style changes such as exercise have also recently been shown to rescue age-related blood flow deficits in the CC. 40…”

Section: Discussionmentioning

confidence: 99%

Impaired drainage through capillary-venous networks contributes to age-related white matter loss

Stamenkovic,

Schmid,

Weitermann

et al. 2024

Preprint

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“…Further, deep two-photon imaging in awake mice showed age-related hypoperfusion was greatest in the callosal white matter 44 . Thus, brain location may be key during studies to relate capillary regression with cerebral blood flow.…”

Section: Discussionmentioning

confidence: 94%

“…However, cortical depth analysis revealed that deeper cortical layers (Layer 5) exhibit more severe capillary rarefaction and is in fact associated with ACT vasoconstriction 42 . Further, deep two-photon imaging in awake mice showed age-related hypoperfusion was greatest in the callosal white matter 43 . Thus, brain location is key during studies to relate capillary regression with cerebral blood flow.…”

Section: Discussionmentioning

confidence: 94%

Capillary regression leads to sustained local hypoperfusion by inducing constriction of upstream transitional vessels

Bonney,

Nielson,

Sosa

et al. 2023

Preprint

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In the brain, a microvascular sensory web coordinates oxygen delivery to regions of neuronal activity. This involves a dense network of capillaries that send conductive signals upstream to feeding arterioles to promote vasodilation and blood flow. Although this process is critical to the metabolic supply of healthy brain tissue, it may also be a point of vulnerability in disease. Deterioration of capillary networks is a hallmark of many neurological disorders and how this web is engaged during vascular damage remains unknown. We performedin vivotwo-photon microscopy on young adult mural cell reporter mice and induced focal capillary injuries using precise two-photon laser irradiation of single capillaries. We found that ∼63% of the injuries resulted in regression of the capillary segment 7-14 days following injury, and the remaining repaired to re-establish blood flow within 7 days. Injuries that resulted in capillary regression induced sustained vasoconstriction in the upstream arteriole-capillary transition (ACT) zone at least 21 days post-injury in both awake and anesthetized mice. This abnormal vasoconstriction involved attenuation of vasomotor dynamics and uncoupling from mural cell calcium signaling following capillary regression. Consequently, blood flow was reduced in the ACT zone and in secondary, uninjured downstream capillaries. These findings demonstrate how capillary injury and regression, as often seen in age-related neurological disease, can impair the microvascular sensory web and contribute to cerebral hypoperfusion.SIGNIFICANCEDeterioration of the capillary network is a characteristic of many neurological diseases and can exacerbate neuronal dysfunction and degeneration due to poor blood perfusion. Here we show that focal capillary injuries can induce vessel regression and elicit sustained vasoconstriction in upstream transitional vessels that branch from cortical penetrating arterioles. This reduces blood flow to broader, uninjured regions of the same microvascular network. These findings suggest that widespread and cumulative damage to brain capillaries in neurological disease may broadly affect blood supply and contribute to hypoperfusion through their remote actions.

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“…Coupled with less efficient on-demand oxygen delivery, these age-related changes will make deep cortical layers highly vulnerable. There is evidence that exercise can help ameliorate age-related declines in perfusion and oxygenation 107 .…”

Section: Discussionmentioning

confidence: 99%

Aging drives cerebrovascular network remodeling and functional changes in the mouse brain

Bennett

Zhang

et al. 2023

Preprint

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Aging is the largest risk factor for neurodegenerative disorders, and commonly associated with compromised cerebrovasculature and pericytes. However, we do not know how normal aging differentially impacts the vascular structure and function in different brain areas. Here we utilize mesoscale microscopy methods (serial two-photon tomography and light sheet microscopy) and in vivo imaging (wide field optical spectroscopy and two-photon imaging) to determine detailed changes in aged cerebrovascular networks. Whole-brain vascular tracing showed an overall ~10% decrease in vascular length and branching density, and light sheet imaging with 3D immunolabeling revealed increased arteriole tortuosity in aged brains. Vasculature and pericyte densities showed significant reductions in the deep cortical layers, hippocampal network, and basal forebrain areas. Moreover, in vivo imaging in awake mice identified delays in neurovascular coupling and disrupted blood oxygenation. Collectively, we uncover regional vulnerabilities of cerebrovascular network and physiological changes that can mediate cognitive decline in normal aging.

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Aerobic exercise reverses aging-induced depth-dependent decline in cerebral microcirculation

Cited by 3 publications

References 67 publications

Impaired drainage through capillary-venous networks contributes to age-related white matter loss

Impaired drainage through capillary-venous networks contributes to age-related white matter loss

Capillary regression leads to sustained local hypoperfusion by inducing constriction of upstream transitional vessels

Aging drives cerebrovascular network remodeling and functional changes in the mouse brain

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