The Neurovascular Unit: Focus on the Regulation of Arterial Smooth Muscle Cells

Quelhas, Patrícia; Baltazar, Graça; Cairrão, Elisa

doi:10.2174/1567202616666191026122642

Cited by 12 publications

(7 citation statements)

References 137 publications

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“…While peripheral organs allow less restricted entry and exit of substances in the blood circulation, the brain's vasculature is protected structurally by components of the blood-brain barrier (BBB) that allow very restricted entry of blood contents into the brain [5][6][7] . The brain vasculature is also different from the vasculature of other organs as it consists of the neurovascular unit (NVU) which is made up of various cell types consisting of vascular (i.e., endothelial cells, pericytes, smooth muscle cells, and perivascular macrophages) and brain (i.e., astrocytes and neurons) cells 8,9 .…”

Section: Introductionmentioning

confidence: 99%

Capillary-associated microglia regulate vascular structure and function through PANX1-P2RY12 coupling

Bisht

Okojie

Sharma

et al. 2021

Preprint

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Microglia are brain-resident immune cells with a repertoire of functions in the developing, mature and pathological brain. Their wide-ranging roles in physiology include the clearance of cellular debris, elimination of excess synapses, regulation of neuronal activity and contributions to blood vessel development. Despite these known roles for microglia, the extent of their interactions with the vasculature and potential regulation of vascular physiology has been insufficiently explored. Here, using in vivo acute and longitudinal two-photon imaging in transgenic mice combined with electron microscopy, fixed tissue immunohistochemistry, pharmacological treatments and laser speckle imaging, we document the steady-state interactions between ramified CX3CR1+ myeloid cell somata and capillaries in the brain. We first confirm that these myeloid cells are bona fide microglia by molecular, morphological and ultrastructural approaches. Then we give a detailed spatio-temporal characterization of these capillary-associated microglia (CAMs) comparing and contrasting them with parenchymal microglia (PCMs) in their static, dynamic and chronic morphological activities including during microglial depletion and repopulation. Molecularly, we identify microglial-specific purinergic P2RY12 receptors as a receptor regulating CAM interactions under the control of released purines from pannexin 1 (PANX1) channels. Furthermore, to elucidate roles for microglia in vascular structure and function, we eliminated microglia and showed that this triggered capillary dilation, blood flow increase, and impaired vasodilative responses. We find that P2RY12-/- and PANX1-/- mice recapitulate these vascular impairments suggesting purines released through PANX1 channels play important roles in activating microglial P2RY12 receptors to regulate neurovascular structure and function.

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Section: Introductionmentioning

confidence: 99%

Capillary-associated microglia regulate vascular structure and function through PANX1-P2RY12 coupling

Bisht

Okojie

Sharma

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…While peripheral organs allow less restricted entry and exit of substances in the blood circulation, the brain's vasculature is protected structurally by components of the blood-brain barrier (BBB) that allow very restricted entry of blood contents into the brain [5][6][7] . The brain vasculature is also different from the vasculature of other organs as it consists of the neurovascular unit (NVU), which is made up of various cell types consisting of vascular (i.e., endothelial cells, pericytes, smooth muscle cells, and perivascular macrophages (PVMs)) and brain (i.e., astrocytes and neurons) cells 8,9 .…”

mentioning

confidence: 99%

Capillary-associated microglia regulate vascular structure and function through PANX1-P2RY12 coupling in mice

et al. 2021

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Microglia are brain-resident immune cells with a repertoire of functions in the brain. However, the extent of their interactions with the vasculature and potential regulation of vascular physiology has been insufficiently explored. Here, we document interactions between ramified CX3CR1 + myeloid cell somata and brain capillaries. We confirm that these cells are bona fide microglia by molecular, morphological and ultrastructural approaches. Then, we give a detailed spatio-temporal characterization of these capillary-associated microglia (CAMs) comparing them with parenchymal microglia (PCMs) in their morphological activities including during microglial depletion and repopulation. Molecularly, we identify P2RY12 receptors as a regulator of CAM interactions under the control of released purines from pannexin 1 (PANX1) channels. Furthermore, microglial elimination triggered capillary dilation, blood flow increase, and impaired vasodilation that were recapitulated in P2RY12−/− and PANX1−/− mice suggesting purines released through PANX1 channels play important roles in activating microglial P2RY12 receptors to regulate neurovascular structure and function.

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“…The concept of an NVU [exhaustively reviewed in ( 49 )] encompasses these varieties of cells and their function, the interactions of which maintain the ionic, metabolic, and molecular homeostasis of the brain. In particular, the neuronal and astrocytic activity is able to provoke a dilation or a contraction of the arterial vessels [executed by smooth muscle cells ( 50 )] or capillaries [provided by pericytes, being an integral part of NVU ( 51 )] via a number of mediator substances, the release of which is strictly dependent on neuronal or astrocytic activity. This list includes not only the nitric oxide (NO), as the prime example of vasoactive substance ( 52 , 53 ), but also products of cyclooxygenase-2 activity (prostanoids) ( 54 , 55 ), D-serine of astrocytic origin ( 56 ), peptide-based vasoactive mediators including vasopressin ( 57 ), somatostatin ( 58 ), neuropeptide Y (NPY) ( 59 , 60 ), and vasoactive intestinal peptide (VIP) ( 61 ), all of which the neurons or astrocytes are capable of secreting.…”

Section: Concepts Of Cerebral Integrated Water Spacementioning

confidence: 99%

Cerebral Microcirculation, Perivascular Unit, and Glymphatic System: Role of Aquaporin-4 as the Gatekeeper for Water Homeostasis

et al. 2021

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In the past, water homeostasis of the brain was understood as a certain quantitative equilibrium of water content between intravascular, interstitial, and intracellular spaces governed mostly by hydrostatic effects i.e., strictly by physical laws. The recent achievements in molecular bioscience have led to substantial changes in this regard. Some new concepts elaborate the idea that all compartments involved in cerebral fluid homeostasis create a functional continuum with an active and precise regulation of fluid exchange between them rather than only serving as separate fluid receptacles with mere passive diffusion mechanisms, based on hydrostatic pressure. According to these concepts, aquaporin-4 (AQP4) plays the central role in cerebral fluid homeostasis, acting as a water channel protein. The AQP4 not only enables water permeability through the blood-brain barrier but also regulates water exchange between perivascular spaces and the rest of the glymphatic system, described as pan-cerebral fluid pathway interlacing macroscopic cerebrospinal fluid (CSF) spaces with the interstitial fluid of brain tissue. With regards to this, AQP4 makes water shift strongly dependent on active processes including changes in cerebral microcirculation and autoregulation of brain vessels capacity. In this paper, the role of the AQP4 as the gatekeeper, regulating the water exchange between intracellular space, glymphatic system (including the so-called neurovascular units), and intravascular compartment is reviewed. In addition, the new concepts of brain edema as a misbalance in water homeostasis are critically appraised based on the newly described role of AQP4 for fluid permeation. Finally, the relevance of these hypotheses for clinical conditions (including brain trauma and stroke) and for both new and old therapy concepts are analyzed.

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The Neurovascular Unit: Focus on the Regulation of Arterial Smooth Muscle Cells

Cited by 12 publications

References 137 publications

Capillary-associated microglia regulate vascular structure and function through PANX1-P2RY12 coupling

Capillary-associated microglia regulate vascular structure and function through PANX1-P2RY12 coupling

Capillary-associated microglia regulate vascular structure and function through PANX1-P2RY12 coupling in mice

Cerebral Microcirculation, Perivascular Unit, and Glymphatic System: Role of Aquaporin-4 as the Gatekeeper for Water Homeostasis

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