Publications by authors named "Fabrice Dabertrand"

Article Synopsis
  • - Microglia are the central nervous system's immune cells, playing essential roles in brain development and maintaining neuron activity, but their involvement at the blood-brain barrier (BBB) in healthy brains is less understood.
  • - A study using the CSF1R inhibitor PLX5622 to deplete microglia showed that they are not crucial for maintaining the structure or function of the healthy BBB, despite their close contact with endothelial cells.
  • - However, treatment with PLX5622 was found to affect cholesterol metabolism in brain endothelial cells independently of microglial presence, indicating that the drug has unintended effects on brain blood vessels.
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Objective: We aimed to investigate if ex vivo plasma from injured patients causes endothelial calcium (Ca2+) influx as a mechanism of trauma-induced endothelial permeability.

Summary Background Data: Endothelial permeability after trauma contributes to post-injury organ dysfunction. While the mechanisms remain unclear, emerging evidence suggests intracellular Ca2+ signaling may play a role.

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Arteries and arterioles exhibit myogenic tone, a partially constricted state that allows further constriction or dilation in response to moment-to-moment fluctuations in blood pressure. The vascular endothelium that lines the internal surface of all blood vessels controls a wide variety of essential functions, including the contractility of the adjacent smooth muscle cells by providing a tonic vasodilatory influence. Studies conducted on large (pial) arteries on the surface of the brain have shown that estrogen lowers myogenic tone in female mice by enhancing nitric oxide (NO) release from the endothelium, however, whether this difference extends to the intracerebral microcirculation remains ambiguous.

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Significance: Vascular mural cells, defined as smooth muscle cells (SMCs) and pericytes, influence brain microcirculation, but how they contribute is not fully understood. Most approaches used to investigate pericyte and capillary interactions include retinal/slice preparations or two-photon microscopy. However, neither method adequately captures mural cell behavior without interfering neuronal tissue.

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Article Synopsis
  • Prostaglandin E (PGE) is thought to help regulate blood flow in the brain by dilating arterioles through EP4 receptors, but previous evidence suggests it may cause constriction via EP1 receptors instead.
  • Recent experiments demonstrated that applying PGE to capillaries leads to dilation of upstream arterioles, with a critical concentration required for this effect and partial inhibition by blocking certain ion channels.
  • A genetic mouse model with cerebral small vessel disease showed diminished responses to PGE stimulation, reinforcing the idea that capillaries play a central role in mediating blood flow responses in the brain.
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Dementia resulting from small vessel diseases (SVDs) of the brain is an emerging epidemic for which there is no treatment. Hypertension is the major risk factor for SVDs, but how hypertension damages the brain microcirculation is unclear. Here, we show that chronic hypertension in a mouse model progressively disrupts on-demand delivery of blood to metabolically active areas of the brain (functional hyperemia) through diminished activity of the capillary endothelial cell inward-rectifier potassium channel, Kir2.

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Cerebral small vessel diseases (SVDs) are a central link between stroke and dementia-two comorbidities without specific treatments. Despite the emerging consensus that SVDs are initiated in the endothelium, the early mechanisms remain largely unknown. Deficits in on-demand delivery of blood to active brain regions (functional hyperemia) are early manifestations of the underlying pathogenesis.

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Vascular cognitive impairment, the second most common cause of dementia, profoundly affects hippocampal-dependent functions. However, while the growing literature covers complex neuronal interactions, little is known about the sustaining hippocampal microcirculation. Here we examined vasoconstriction to physiological pressures of hippocampal arterioles, a fundamental feature of small arteries, in a genetic mouse model of CADASIL, an archetypal cerebral small vessel disease.

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Neuronal activity leads to an increase in local cerebral blood flow (CBF) to allow adequate supply of oxygen and nutrients to active neurons, a process termed neurovascular coupling (NVC). We have previously shown that capillary endothelial cell (cEC) inwardly rectifying K (Kir) channels can sense neuronally evoked increases in interstitial K and induce rapid and robust dilations of upstream parenchymal arterioles, suggesting a key role of cECs in NVC. The requirements of this signal conduction remain elusive.

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Background: Spontaneous deep intracerebral hemorrhage (ICH) is a devastating subtype of stroke without specific treatments. It has been thought that smooth muscle cell (SMC) degeneration at the site of arteriolar wall rupture may be sufficient to cause hemorrhage. However, deep ICHs are rare in some aggressive small vessel diseases that are characterized by significant arteriolar SMC degeneration.

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From subtle behavioral alterations to late-stage dementia, vascular cognitive impairment typically develops following cerebral ischemia. Stroke and cardiac arrest are remarkably sexually dimorphic diseases, and both induce cerebral ischemia. However, progress in understanding the vascular cognitive impairment, and then developing sex-specific treatments, has been partly limited by challenges in investigating the brain microcirculation from mouse models in functional studies.

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Brain capillaries play a critical role in sensing neural activity and translating it into dynamic changes in cerebral blood flow to serve the metabolic needs of the brain. The molecular cornerstone of this mechanism is the capillary endothelial cell inward rectifier K (Kir2.1) channel, which is activated by neuronal activity-dependent increases in external K concentration, producing a propagating hyperpolarizing electrical signal that dilates upstream arterioles.

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Vascular aging fundamentally contributes to large and small vessel disease. Despite the importance of such changes for brain function, mechanisms that mediate such changes are poorly defined. We explored mechanisms that underlie changes with age, testing the hypothesis that ROCK (Rho kinase) plays an important role.

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Cerebral SVDs encompass a group of genetic and sporadic pathological processes leading to brain lesions, cognitive decline, and stroke. There is no specific treatment for SVDs, which progress silently for years before becoming clinically symptomatic. Here, we examine parallels in the functional defects of PAs in CADASIL, a monogenic form of SVD, and in response to SAH, a common type of hemorrhagic stroke that also targets the brain microvasculature.

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Cerebral small vessel disease (SVD) is a leading cause of stroke and dementia. CADASIL, an inherited SVD, alters cerebral artery function, compromising blood flow to the working brain. TIMP3 (tissue inhibitor of metalloproteinase 3) accumulation in the vascular extracellular matrix in CADASIL is a key contributor to cerebrovascular dysfunction.

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Intracerebral parenchymal arterioles (PAs), which include parenchymal arterioles, penetrating arterioles and pre-capillary arterioles, are high resistance blood vessels branching out from pial arteries and arterioles and diving into the brain parenchyma. Individual PA perfuse a discrete cylindrical territory of the parenchyma and the neurons contained within. These arterioles are a central player in the regulation of cerebral blood flow both globally (cerebrovascular autoregulation) and locally (functional hyperemia).

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), caused by dominant mutations in the NOTCH3 receptor in vascular smooth muscle, is a genetic paradigm of small vessel disease (SVD) of the brain. Recent studies using transgenic (Tg)Notch3(R169C) mice, a genetic model of CADASIL, revealed functional defects in cerebral (pial) arteries on the surface of the brain at an early stage of disease progression. Here, using parenchymal arterioles (PAs) from within the brain, we determined the molecular mechanism underlying the early functional deficits associated with this Notch3 mutation.

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Article Synopsis
  • Alternative splicing of the ryanodine receptor subtype 3 (RyR3) leads to a short isoform (RyR3S) that inhibits another subtype, RyR2, which is essential for regulating calcium signaling in cerebral arteries.
  • Research demonstrated that reducing RyR3S using antisense oligonucleotides (asRyR3S) increased calcium signals in mouse smooth muscle cells, suggesting RyR2's key role in vascular function.
  • However, attempts to deliver asRyR3S to cerebral arteries in vivo, using various methods to disrupt the blood-brain barrier, were unsuccessful, indicating that while RyR3S may operate in isolated conditions, targeting it in live subjects remains challenging.
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Maintaining constant blood flow in the face of fluctuations in blood pressure is a critical autoregulatory feature of cerebral arteries. An increase in pressure within the artery lumen causes the vessel to constrict through depolarization and contraction of the encircling smooth muscle cells. This pressure-sensing mechanism involves activation of two types of transient receptor potential (TRP) channels: TRPC6 and TRPM4.

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Studies of stress effects on the brain have traditionally focused on neurons, without considering the cerebral microcirculation. Here we report that stress impairs neurovascular coupling (NVC), the process that matches neuronal activity with increased local blood flow. A stressed phenotype was induced in male rats by administering a 7-d heterotypical stress paradigm.

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