The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease

Iadecola, Costantino

doi:10.1016/j.neuron.2017.07.030

Cited by 1,733 publications

(1,780 citation statements)

References 252 publications

(411 reference statements)

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“…Normal cognition function requires an adequate, well-regulated delivery of blood flow 13 . Therefore, we investigated whether the neurovascular dysfunction induced by HSD leads to cognitive impairment.…”

Section: Resultsmentioning

confidence: 99%

“…However, it is not known how excess dietary salt leads to such NO deficit or whether the resulting vascular changes in the long run impair organ function. These unanswered questions are particularly relevant for the brain, an organ that relies critically on a continuous delivery of blood flow well matched to its dynamic energy needs 13 . Alterations in resting cerebral blood flow (CBF) and its regulation are well known to produce neuronal dysfunction and cognitive impairment 14 and could play a role in the harmful effects of excessive salt intake on the brain.…”

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confidence: 99%

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Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response

et al. 2018

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A diet rich in salt is linked to an increased risk of cerebrovascular diseases and dementia, but it remains unclear how dietary salt harms the brain. We report that, in mice, excess dietary salt suppresses resting cerebral blood flow and endothelial function, leading to cognitive impairment. The effect depends on expansion of TH17 cells in the small intestine, resulting in a marked increase in plasma interleukin-17 (IL-17). Circulating IL-17, in turn, promotes endothelial dysfunction and cognitive impairment by the Rho kinase-dependent inhibitory phosphorylation of endothelial nitric oxide synthase and reduced nitric oxide production in cerebral endothelial cells. The findings reveal a new gut-brain axis linking dietary habits to cognitive impairment through a gut-initiated adaptive immune response compromising brain function via circulating IL-17. Thus, the TH17 cell-IL-17 pathway is a putative target to counter the deleterious brain effects induced by dietary salt and other diseases associated with TH17 polarization.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response

et al. 2018

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“…Tight junctions between endothelial cells, a defining feature of the BBB, serve to block the diffusion of hydrophilic or large molecules, as well as microscopic particles into the cerebrospinal fluid. The current understanding of the BBB views it as one aspect of the dynamic neurovascular unit (NVU), comprising endothelial cells, surrounding vascular smooth muscle cells or pericytes, basement membranes, and astrocyte end-feet processes and neuronal projections (Iadecola, 2017). The NVU functions to regulate communication between the brain and cerebrovascular network, most notably in the context of coupling neuronal activity to blood flow.…”

Section: Background and Rationale For Immunomodulatory Stroke Therapymentioning

confidence: 99%

Targeting vascular inflammation in ischemic stroke: Recent developments on novel immunomodulatory approaches

Shekhar

Cunningham

Pabbidi

et al. 2018

European Journal of Pharmacology

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Ischemic stroke is a devastating and debilitating medical condition with limited therapeutic options. However, accumulating evidence indicates a central role of inflammation in all aspects of stroke including its initiation, the progression of injury, and recovery or wound healing. A central target of inflammation is disruption of the blood brain barrier or neurovascular unit. Here we discuss recent developments in identifying potential molecular targets and immunomodulatory approaches to preserve or protect barrier function and limit infarct damage and functional impairment. These include blocking harmful inflammatory signaling in endothelial cells, microglia/macrophages, or Th17/γδ T cells with biologics, third generation epoxyeicosatrienoic acid (EET) analogs with extended half-life, and miRNA antagomirs. Complementary beneficial pathways may be enhanced by miRNA mimetics or hyperbaric oxygenation. These immunomodulatory approaches could be used to greatly expand the therapeutic window for thrombolytic treatment with tissue plasminogen activator (t-PA). Moreover, nanoparticle technology allows for the selective targeting of endothelial cells for delivery of DNA/RNA oligonucleotides and neuroprotective drugs. In addition, although likely detrimental to the progression of ischemic stroke by inducing inflammation, oxidative stress, and neuronal cell death, 20-HETE may also reduce susceptibility of onset of ischemic stroke by maintaining autoregulation of cerebral blood flow. Although the interaction between inflammation and stroke is multifaceted, a better understanding of the mechanisms behind the pro-inflammatory state at all stages will hopefully help in developing novel immunomodulatory approaches to improve mortality and functional outcome of those inflicted with ischemic stroke.

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“…All failures of major organs lead to different degrees of cognitive impairment. Heart failure constitutes the most prevalent . Kidney failure represents another common example, the cognitive status often fluctuating with the dates of dialysis.…”

Section: Challengesmentioning

confidence: 99%

Implementing the proclamation of stroke and potentially preventable dementias

Hachinski

Ganten

Lackland

et al. 2018

J of Clinical Hypertension

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Brain health plays a central role in well‐being and in the management of chronic diseases. Stroke and dementia pose the two greatest threats to brain health, but recent developments suggest the possibility that preventing stroke may also prevent some dementias: (a) A large population study showed a 32% decrease in the incidence of stroke and a concomitant 7% reduction in the incidence of dementia; (b) the treatment of atrial fibrillation resulted not only in stroke reduction, but also a 48% decrease in dementia; (c) the hypothesis‐free analyses have shown that the first phase of Alzheimer disease involves vascular dysregulation, opening the door to new therapeutic approaches; (d) cognitive impairment, often treatable and reversible, accompanies heart and kidney failure. These developments, combined with the knowledge that stroke, dementia, and heart disease share the same major treatable risk factors, particularly hypertension, offer an opportunity for their joint prevention. This aspiration is expressed by a Proclamation of the World Stroke Organization on Stroke and Potentially Preventable Dementias and endorsed by the World Heart Federation, the World Hypertension League, Alzheimer Disease International, and 18 other international, regional, and national organizations as a call for action.

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The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease

Cited by 1,733 publications

References 252 publications

Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response

Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response

Targeting vascular inflammation in ischemic stroke: Recent developments on novel immunomodulatory approaches

Implementing the proclamation of stroke and potentially preventable dementias

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