Microglia control cerebral blood flow and neurovascular coupling via P2Y12R-mediated actions

Császár, Eszter; Lénárt, Nikolett; Cserép, Csaba; Környei, Zsuzsanna; Fekete, Rebeka; Pósfai, Balázs; Balázsfi, Diána; Hangya, Balázs; Schwarcz, Anett D.; Szöllősi, Dávid; Szigeti, Krisztián; Máthé, Domokos; West, Brian L.; Sviatkó, Katalin; Brás, Ana Rita; Mariani, Jean-Charles; Kliewer, Andrea; Lenkei, Zsolt; Hricisák, László; Benyó, Zoltán; Baranyi, Mária; Sperlágh, Beáta; Menyhárt, Ákos; Farkas, Eszter

doi:10.1101/2021.02.04.429741

Cited by 19 publications

(31 citation statements)

References 94 publications

(154 reference statements)

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“…This vasculogenic role of microglia is underscored by the finding that microglia-deficient mice display impaired angiogenesis ( Fantin et al, 2010 ). A recent study has also discovered an as-yet unappreciated role for microglia in regulating CBF; depletion of microglia or a microglia-specific knock-out of P2Y12R, a purinergic receptor characteristic of “resting” microglia in adult animals, resulted in a small but significant decrease in NVC and cerebrovascular reactivity ( Császár et al, 2021 , preprint). As monocyte-related cells, microglia also serve essential functions as the resident immune cells of the brain.…”

Section: Neurovascular Unit: Components and Developmentmentioning

confidence: 99%

Neurovascular Coupling in Development and Disease: Focus on Astrocytes

Stackhouse

Mishra

2021

Front. Cell Dev. Biol.

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Neurovascular coupling is a crucial mechanism that matches the high energy demand of the brain with a supply of energy substrates from the blood. Signaling within the neurovascular unit is responsible for activity-dependent changes in cerebral blood flow. The strength and reliability of neurovascular coupling form the basis of non-invasive human neuroimaging techniques, including blood oxygen level dependent (BOLD) functional magnetic resonance imaging. Interestingly, BOLD signals are negative in infants, indicating a mismatch between metabolism and blood flow upon neural activation; this response is the opposite of that observed in healthy adults where activity evokes a large oversupply of blood flow. Negative neurovascular coupling has also been observed in rodents at early postnatal stages, further implying that this is a process that matures during development. This rationale is consistent with the morphological maturation of the neurovascular unit, which occurs over a similar time frame. While neurons differentiate before birth, astrocytes differentiate postnatally in rodents and the maturation of their complex morphology during the first few weeks of life links them with synapses and the vasculature. The vascular network is also incomplete in neonates and matures in parallel with astrocytes. Here, we review the timeline of the structural maturation of the neurovascular unit with special emphasis on astrocytes and the vascular tree and what it implies for functional maturation of neurovascular coupling. We also discuss similarities between immature astrocytes during development and reactive astrocytes in disease, which are relevant to neurovascular coupling. Finally, we close by pointing out current gaps in knowledge that must be addressed to fully elucidate the mechanisms underlying neurovascular coupling maturation, with the expectation that this may also clarify astrocyte-dependent mechanisms of cerebrovascular impairment in neurodegenerative conditions in which reduced or negative neurovascular coupling is noted, such as stroke and Alzheimer’s disease.

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Section: Neurovascular Unit: Components and Developmentmentioning

confidence: 99%

Neurovascular Coupling in Development and Disease: Focus on Astrocytes

Stackhouse

Mishra

2021

Front. Cell Dev. Biol.

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“…Multi-photon microscopy (MPM) is the “gold standard” for the study of cellular dynamics, function and morphology as well as hemodynamics (Shih et al, 2012 ; O'Herron et al, 2016 ; Urban et al, 2017 ) in a low- to non-invasive way [i.e., cranial window (Goldey et al, 2014 ), thinned-skull (Drew et al, 2010 ), or transcranial (Wang et al, 2018 )]. The capabilities of MPM (Urban et al, 2017 ; Li B. et al, 2020 ) combined with cell-specific genetically encoded activity reporters suited for probing either calcium or voltage changes (GECIs and GEVIs) (Lin and Schnitzer, 2016 ) has allowed the simultaneous recording of many cell populations involved in NVC [neurons (Urban et al, 2017 ), roles of astrocytes in the control of arteriole diameter, increase in local blood flow (Takano et al, 2006 ; Tran and Gordon, 2015 ), microglia as important regulators of blood flow during NVC (Hierro-Bujalance et al, 2018 ; Császár et al, 2021 ), pericytes control blood flow direction at capillary junctions, maintenance of capillary flow resistance and metabolic exchanges (Berthiaume et al, 2018 ; Gonzales et al, 2020 )] and/or BBB permeability (Knowland et al, 2014 ). Along with cell-specific imaging, MPM can record local volumetric hemodynamic changes [blood flow and red blood cell velocity (Urban et al, 2017 )] from surface pial vessels down to deep capillaries (Fan et al, 2020 ) with dedicated circulating fluorescent contrast agents (Miller et al, 2017 ).…”

Section: Tools To Study Regional Heterogeneity Of the Nvumentioning

confidence: 99%

Location Matters: Navigating Regional Heterogeneity of the Neurovascular Unit

Bernier

Brunner

Cottarelli

et al. 2021

Front. Cell. Neurosci.

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The neurovascular unit (NVU) of the brain is composed of multiple cell types that act synergistically to modify blood flow to locally match the energy demand of neural activity, as well as to maintain the integrity of the blood-brain barrier (BBB). It is becoming increasingly recognized that the functional specialization, as well as the cellular composition of the NVU varies spatially. This heterogeneity is encountered as variations in vascular and perivascular cells along the arteriole-capillary-venule axis, as well as through differences in NVU composition throughout anatomical regions of the brain. Given the wide variations in metabolic demands between brain regions, especially those of gray vs. white matter, the spatial heterogeneity of the NVU is critical to brain function. Here we review recent evidence demonstrating regional specialization of the NVU between brain regions, by focusing on the heterogeneity of its individual cellular components and briefly discussing novel approaches to investigate NVU diversity.

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“…Whereas microglia are the main regulators of inflammatory processes in the brain, their role in NVC is not well defined. However, recently, they were suggested as essential in regulating CBF during neural activation (Császár et al, 2021). Brain ECs have unique morphological and functional features such as a lack of fenestration, the presence of tight junctions between cells, a low number of pinocytic vesicles that limit transcytosis, hence forming the first limiting layer of the BBB (Reese and Karnovsky, 1967;Stamatovic et al, 2008;Rizzo and Leaver, 2010;Salmina et al, 2014;Andreone et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

From Neurodevelopmental to Neurodegenerative Disorders: The Vascular Continuum

Ouellette

Lacoste

2021

Front. Aging Neurosci.

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Structural and functional integrity of the cerebral vasculature ensures proper brain development and function, as well as healthy aging. The inability of the brain to store energy makes it exceptionally dependent on an adequate supply of oxygen and nutrients from the blood stream for matching colossal demands of neural and glial cells. Key vascular features including a dense vasculature, a tightly controlled environment, and the regulation of cerebral blood flow (CBF) all take part in brain health throughout life. As such, healthy brain development and aging are both ensured by the anatomical and functional interaction between the vascular and nervous systems that are established during brain development and maintained throughout the lifespan. During critical periods of brain development, vascular networks remodel until they can actively respond to increases in neural activity through neurovascular coupling, which makes the brain particularly vulnerable to neurovascular alterations. The brain vasculature has been strongly associated with the onset and/or progression of conditions associated with aging, and more recently with neurodevelopmental disorders. Our understanding of cerebrovascular contributions to neurological disorders is rapidly evolving, and increasing evidence shows that deficits in angiogenesis, CBF and the blood-brain barrier (BBB) are causally linked to cognitive impairment. Moreover, it is of utmost curiosity that although neurodevelopmental and neurodegenerative disorders express different clinical features at different stages of life, they share similar vascular abnormalities. In this review, we present an overview of vascular dysfunctions associated with neurodevelopmental (autism spectrum disorders, schizophrenia, Down Syndrome) and neurodegenerative (multiple sclerosis, Huntington’s, Parkinson’s, and Alzheimer’s diseases) disorders, with a focus on impairments in angiogenesis, CBF and the BBB. Finally, we discuss the impact of early vascular impairments on the expression of neurodegenerative diseases.

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Microglia control cerebral blood flow and neurovascular coupling via P2Y12R-mediated actions

Cited by 19 publications

References 94 publications

Neurovascular Coupling in Development and Disease: Focus on Astrocytes

Neurovascular Coupling in Development and Disease: Focus on Astrocytes

Location Matters: Navigating Regional Heterogeneity of the Neurovascular Unit

From Neurodevelopmental to Neurodegenerative Disorders: The Vascular Continuum

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