NEUVASCHEMIA

Neurovascular coupling in stroke - the brain microvasculature as a target for prevention of ischemic brain damage

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 Obiettivo del progetto (Objective)

'What happens in the small brain blood vessels and surrounding neurons and glia cells (the neurovascular unit) after a stroke? Can we therapeutically prevent this pathology to normalise blood flow regulation and improve outcome after stroke? These questions are at the heart of my proposal. Current treatment options for stroke - the leading cause of long-term disabilities in Europe - are remarkably limited. Numerous failed clinical trials suggest that merely neuroprotective drugs are insufficient. We must understand and treat pathological changes in the neurovascular unit as a whole. The study of molecular mechanisms governing the interaction between brain arterioles, neurons and glia cells (neurovascular coupling) has been halted by the lack of appropriate techniques. However, in recent years novel techniques have been developed, and an exciting research field is emerging – with the Nelson lab at University of Vermont as a front-runner. However, the novel techniques and knowledge have not yet been exploited to study neurovascular pathology in stroke – the main objective of my proposal. I will use advanced techniques in the Nelson lab to investigate alterations in a) neurovascular coupling in vivo, b) contractile function of small brain arterioles and c) intracellular calcium signals in these vessels and surrounding astrocytes after ischemic stroke in mice. I will then transfer key techniques to the return lab and use them together with quantitative mass spectrometry (proteomics) to test whether inhibition of a central intracellular signalling pathway activated in brain vessels after stroke can prevent pathology in the neurovascular unit and improve outcome. This will provide novel information on neurovascular coupling deficits in stroke and possible therapeutic targets. It will increase European excellence in neurovascular coupling by transferring frontier technical and scientific skills to Europe and fostering novel transatlantic collaborations.'

Introduzione (Teaser)

Every three minutes, someone dies from a stroke when the blood supply to the brain is disrupted. An EU-funded project explored the underlying mechanisms of stroke with the goal of identifying new treatments.

Descrizione progetto (Article)

According to the European Heart Network, stroke is the second most common cause of death in Europe and the leading cause of long-term disabilities.

An ageing European population means that the human and economic costs of stroke are likely to increase significantly.To address this problem, thie 'Neurovascular coupling in stroke--the brain microvasculature as a target for prevention of ischemic brain damage' (NEUVASCHEMIA) project looked at a key mechanism--regulating blood circulation in the days following a stroke.

Earlier research had shown that pial arteries in the brain stimulate some receptors that inhibit blood flow after a stroke, leading to decreased cerebral circulation.

However, pial arteries contribute only half of the vascular resistance in the brain.

The other half comes from branches called brain parenchymal arterioles.

When the brain is busy with a cognitive task, the local brain cells, called astrocytes, signal that increased blood flow is needed through extensions called endfeet.

This process, called neurovascular coupling, serves to increase blood flow.

Understanding the mechanisms controlling neurovascular coupling was the focus of this research.Experiments involved comparing neurovascular coupling in acute brain slices from sham-operated rats (the control group) and rats induced with global cerebral ischemia, or restricted blood circulation.

To initiate neurovascular coupling, brain slices loaded with the calcium indicator Fluo-4 were stimulated through electrical fields.

Researchers then measured the calcium signals in the astrocytic endfeet and diameter changes of the parenchymal arterioles in response to neuronal stimulation. The results showed that neurovascular coupling no longer occurred in rats subjected to global cerebral ischemia.

To further understand why, researchers analysed each part of the process.

They found that calcium signals were unchanged, but there was reduced function of potassium channels in the small muscle layer of the cerebral parenchymal arterioles.

These channels play a key role in supplying brain tissue with blood.

This discovery deepened understanding of the molecular mechanisms responsible for preventing neurovascular coupling.

It could lead to new therapeutic strategies targeting the cerebrovascular system.