Precapillary sphincters maintain perfusion in the cerebral cortex

Grubb, Søren; Cai, Changsi; Hald, Bjørn Olav; Khennouf, Lila; Murmu, Reena Prity; Jensen, Aske G. K.; Fordsmann, Jonas Christoffer; Zambach, Stefan Andreas; Lauritzen, Martin

doi:10.1038/s41467-020-14330-z

Cited by 126 publications

(205 citation statements)

References 52 publications

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“…The definition of the vessels, however, has varied depending on the studies. While some studies have defined all vessels including proximal and distal branches coming off penetrating arterioles as capillaries (Peppiatt et al, 2006;Hall et al, 2014;Cai et al, 2018;Khennouf et al, 2018;Grubb et al, 2020), others have defined proximal branches as precapillary arterioles (Fernández-Klett et al, 2010;Hartmann et al, 2015;Hill et al, 2015). To make matters more complicated, Hill et al (2015), have asserted that the mural cells on the proximal FIGURE 1 | Brain vessels and mural cells.…”

Section: Mural Cells In the Brain Small Vessels: Vascular Smooth Muscmentioning

confidence: 99%

“…Because these pericytes are positioned at the transition between arterioles and capillaries, and have shared some characteristics with SMCs, the terminology and classification of these mural cells have been hotly debated. The cells have been variably called as ensheathing pericytes Grant et al, 2019), transition/transitional pericytes (Kisler et al, 2017a;Arango-Lievano et al, 2018), pre-capillary pericytes (Zimmermann, 1923), simply 'pericytes' or 'capillary pericytes' (Hall et al, 2014;Attwell et al, 2016;Cai et al, 2018;Khennouf et al, 2018;Grubb et al, 2020), smooth muscle-pericyte hybrids (Hartmann et al, 2015;Yang et al, 2017;Dalkara, 2019), arteriole SMC (aaSMC) (Vanlandewijck et al, 2018), or pre-capillary SMCs (Hill et al, 2015). At the same time, the vessels of proximal branches coming off penetrating arterioles are also differently defined as pre-capillary arterioles (Fernández-Klett et al, 2010;Hartmann et al, 2015;Hill et al, 2015;Berthiaume et al, 2018;Erdener and Dalkara, 2019;Grant et al, 2019), post-arteriole capillaries (Gould et al, 2016) or a part of capillaries (Hall et al, 2014;Attwell et al, 2016;Cai et al, 2018;Khennouf et al, 2018;Grubb et al, 2020).…”

Section: Pericytes In the Proximal Capillariesmentioning

confidence: 99%

“…The cells in this proximal branches (especially, 1st to 2nd branches) coming off arterioles has drawn attention as they highly contribute to neurovascular coupling (NVC) (Hall et al, 2014;Hill et al, 2015;Cai et al, 2018;Khennouf et al, 2018;Rungta et al, 2018;Grubb et al, 2020) and no-reflow phenomenon after acute ischemia (Hall et al, 2014;Hill et al, 2015). Although referring to these mural cells as a subtype of "pericytes" has become almost a consensus, the shifting nomenclature of these cells and vessels has been the root of recent controversies on pericyte roles as regulators of CBF (discussed below).…”

Section: Pericytes In the Proximal Capillariesmentioning

confidence: 99%

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Brain Microvascular Pericytes in Vascular Cognitive Impairment and Dementia

Uemura

Maki

Ihara

et al. 2020

Front. Aging Neurosci.

169

112

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Pericytes are unique, multi-functional mural cells localized at the abluminal side of the perivascular space in microvessels. Originally discovered in 19th century, pericytes had drawn less attention until decades ago mainly due to lack of specific markers. Recently, however, a growing body of evidence has revealed that pericytes play various important roles: development and maintenance of blood-brain barrier (BBB), regulation of the neurovascular system (e.g., vascular stability, vessel formation, cerebral blood flow, etc.), trafficking of inflammatory cells, clearance of toxic waste products from the brain, and acquisition of stem cell-like properties. In the neurovascular unit, pericytes perform these functions through coordinated crosstalk with neighboring cells including endothelial, glial, and neuronal cells. Dysfunction of pericytes contribute to a wide variety of diseases that lead to cognitive impairments such as cerebral small vessel disease (SVD), acute stroke, Alzheimer's disease (AD), and other neurological disorders. For instance, in SVDs, pericyte degeneration leads to microvessel instability and demyelination while in stroke, pericyte constriction after ischemia causes a no-reflow phenomenon in brain capillaries. In AD, which shares some common risk factors with vascular dementia, reduction in pericyte coverage and subsequent microvascular impairments are observed in association with white matter attenuation and contribute to impaired cognition. Pericyte loss causes BBB-breakdown, which stagnates amyloid β clearance and the leakage of neurotoxic molecules into the brain parenchyma. In this review, we first summarize the characteristics of brain microvessel pericytes, and their roles in the central nervous system. Then, we focus on how dysfunctional pericytes contribute to the pathogenesis of vascular cognitive impairment including cerebral 'small vessel' and 'large vessel' diseases, as well as AD. Finally, we discuss therapeutic implications for these disorders by targeting pericytes.

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Section: Mural Cells In the Brain Small Vessels: Vascular Smooth Muscmentioning

confidence: 99%

Section: Pericytes In the Proximal Capillariesmentioning

confidence: 99%

Section: Pericytes In the Proximal Capillariesmentioning

confidence: 99%

See 1 more Smart Citation

Brain Microvascular Pericytes in Vascular Cognitive Impairment and Dementia

Uemura

Maki

Ihara

et al. 2020

Front. Aging Neurosci.

169

112

View full text Add to dashboard Cite

show abstract

“…First, using the Cspg4-Cre-Tom line, we anatomically characterized sphincter pericytes. In the brain, they control blood inflow from an artery into a capillary branch [21,38]. We found that this is a single cell fully encircling the opening into the branching vessel; the cell had relatively low SMA expression and was heavily insulated by the basement membrane.…”

Section: Mural Cell-specific Creert2 Lines For Basic Researchmentioning

confidence: 92%

“…Using the Cspg4-Cre-Tom mouse, we evaluated the sphincter cells (Figure 2i-n), a unique structure that is believed to play a role in gating blood inflow into the arterial branch [21][22][23].…”

Section: Identification Of Morphological Polarization Of Mural Cells mentioning

confidence: 99%

Retina-specific targeting of pericytes reveals structural diversity and enables control of capillary blood flow

Ivanova

Corona

Eleftheriou

et al. 2020

Preprint

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Pericytes are a unique class of mural cells essential for angiogenesis, maintenance of the vasculature and are key players in microvascular pathology. However, their diversity and specific roles are poorly understood, limiting our insight into vascular physiology and the ability to develop effective therapies. Here, in the mouse retina, a tractable model of the CNS, we evaluated distinct classes of mural cells along the vascular tree for both structural characterization and physiological manipulation of blood flow. To accomplish this, we first tested three inducible mural cell-specific mouse lines using a sensitive Ai14 reporter and tamoxifen application either by a systemic injection, or by local administration in the form of eye drops. Across three lines, under either the PDGFRb or NG2 promoter, the specificity and pattern of Cre activation varied significantly. In particular, a mouse line with Cre under the NG2 promoter resulted in sparse TdTomato labeling of mural cells, allowing for an unambiguous characterization of anatomical features of individual sphincter cells and capillary pericytes.Furthermore, in one PDGFRb line, we found that focal eye drop application of tamoxifen led to an exclusive Cre-activation in pericytes, without affecting arterial mural cells. We then used this approach to boost capillary blood flow by selective expression of Halorhodopsin, a highly precise hyperpolarizing optogenetic actuator. The ability to exclusively target capillary pericytes may prove a precise and potentially powerful tool to treat microcirculation deficit, a common pathology in numerous diseases. *

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Retina‐specific targeting of pericytes reveals structural diversity and enables control of capillary blood flow

Ivanova

Corona

Eleftheriou

et al. 2020

J of Comparative Neurology

View full text Add to dashboard Cite

Pericytes are a unique class of mural cells essential for angiogenesis, maintenance of the vasculature and are key players in microvascular pathology. However, their diversity and specific roles are poorly understood, limiting our insight into vascular physiology and the ability to develop effective therapies. Here, in the mouse retina, a tractable model of the CNS, we evaluated distinct classes of mural cells along the vascular tree for both structural characterization and physiological manipulation of blood flow. To accomplish this, we first tested three inducible mural cell‐specific mouse lines using a sensitive Ai14 reporter and tamoxifen application either by a systemic injection, or by local administration in the form of eye drops. The specificity and pattern of cre activation varied significantly across the three lines, under either the PDGFRβ or NG2 promoter (Pdgfrβ‐CreRha, Pdgfrβ‐CreCsln, and Cspg4‐Cre). In particular, a mouse line with Cre under the NG2 promoter resulted in sparse TdTomato labeling of mural cells, allowing for an unambiguous characterization of anatomical features of individual sphincter cells and capillary pericytes. Furthermore, in one PDGFRβ line, we found that focal eye drop application of tamoxifen led to an exclusive Cre‐activation in pericytes, without affecting arterial mural cells. We then used this approach to boost capillary blood flow by selective expression of Halorhodopsin, a highly precise hyperpolarizing optogenetic actuator. The ability to exclusively target capillary pericytes may prove a precise and potentially powerful tool to treat microcirculation deficits, a common pathology in numerous diseases.

show abstract

Precapillary sphincters maintain perfusion in the cerebral cortex

Cited by 126 publications

References 52 publications

Brain Microvascular Pericytes in Vascular Cognitive Impairment and Dementia

Brain Microvascular Pericytes in Vascular Cognitive Impairment and Dementia

Retina-specific targeting of pericytes reveals structural diversity and enables control of capillary blood flow

Retina‐specific targeting of pericytes reveals structural diversity and enables control of capillary blood flow

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