Pericyte Loss Leads to Capillary Stalling Through Increased Leukocyte-Endothelial Cell Interaction in the Brain

Choe, Young-Geun; Yoon, Jin-Hui; Joo, JongYoon; Hong, Seon Pyo; Koh, Gou Young; Lee, Dong‐Seok; Oh, Wang‐Yuhl; Jeong, Yong Hoon

doi:10.3389/fncel.2022.848764

Cited by 21 publications

(25 citation statements)

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“…Flow stalls are typically seen in only 0.4% of brain capillaries of healthy adult mice, and an increase to 1.8% in a mouse model of AD was associated with worsened cognitive performance 36 . In agreement with this idea, a recent study using an adult-induced genetic pericyte depletion model also observed increased capillary stalling 43 . This effect was attributed to enhanced leukocyte–endothelial interaction, but may also involve flow steal in capillary networks.…”

Section: Discussionsupporting

confidence: 65%

Pericyte remodeling is deficient in the aged brain and contributes to impaired capillary flow and structure

et al. 2022

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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.

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Section: Discussionsupporting

confidence: 65%

Pericyte remodeling is deficient in the aged brain and contributes to impaired capillary flow and structure

et al. 2022

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“…In a second approach, only diphtheria toxin is genetically expressed in mural cells, including pericytes. This approach also leads to marked loss of pericytes with widespread blood flow deficits and tissue hypoxia, but there is a surprising lack of BBB dysfunction (Park et al, 2017;Choe et al, 2022). This discrepancy may be due to off-target effects of the toxin provided systemically, though more studies are needed.…”

Section: Introductionmentioning

confidence: 99%

In vivo Single Cell Optical Ablation of Brain Pericytes

et al. 2022

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Pericytes have myriad functions in cerebrovascular regulation but remain understudied in the living brain. To dissect pericyte functions in vivo, prior studies have used genetic approaches to induce global pericyte loss in the rodent brain. However, this leads to complex outcomes, making it challenging to disentangle the physiological roles of pericytes from the pathophysiological effects of their depletion. Here, we describe a protocol to optically ablate individual pericytes of the mouse cerebral cortex in vivo for fine-scale studies of pericyte function. The strategy relies on two-photon microscopy and cranial window-implanted transgenic mice with mural cell-specific expression of fluorescent proteins. Single pericyte somata are precisely targeted with pulsed infrared laser light to induce selective pericyte death, but without overt blood-brain barrier leakage. Following pericyte ablation, the changes to the local capillary network and remaining pericytes can be examined longitudinally. The approach has been used to study pericyte roles in capillary flow regulation, and the structural remodeling of pericytes involved in restoration of endothelial coverage after pericyte loss.

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“…36 In agreement with this idea, a recent study using an adult-induced genetic pericyte depletion model also observed increased capillary stalling. 43 This effect was attributed to enhanced leukocyte-endothelial interaction, but may also involve flow steal in capillary networks.…”

Section: Discussionmentioning

confidence: 99%

Pericyte remodeling is deficient in the aged brain and contributes to impaired capillary flow and structure

Berthiaume

Schmid

Stamenković

et al. 2022

Preprint

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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. We conducted cause-and-effect studies by optically ablating pericytes in adult and aged mice in vivo. Focal pericyte loss induced capillary dilation without blood-brain barrier disruption. These abnormal dilations were exacerbated in the aged brain, and resulted in increased flow heterogeneity in capillary networks. A subset of affected capillaries reduced in perfusion due to flow steal. Some capillaries stalled in flow and regressed, leading to loss of capillary connectivity. Remodeling of neighboring pericytes restored endothelial coverage and vascular tone within days. Pericyte remodeling was 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.

show abstract

Pericyte Loss Leads to Capillary Stalling Through Increased Leukocyte-Endothelial Cell Interaction in the Brain

Cited by 21 publications

References 67 publications

Pericyte remodeling is deficient in the aged brain and contributes to impaired capillary flow and structure

Pericyte remodeling is deficient in the aged brain and contributes to impaired capillary flow and structure

In vivo Single Cell Optical Ablation of Brain Pericytes

Pericyte remodeling is deficient in the aged brain and contributes to impaired capillary flow and structure

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