Korte, Nils;
(2021)
Regulation of cerebral blood flow in health, stroke and Alzheimer’s disease.
Doctoral thesis (Ph.D), UCL (University College London).
Abstract
Like a computer, the brain requires a constant supply of energy, in the form of oxygen and glucose in the blood, to maintain ion pumping. However cerebral blood flow (CBF) is reduced in ischaemic stroke and Alzheimer’s disease (AD) because contractile cells called pericytes constrict capillaries. In this thesis, I studied the mechanisms determining pericyte tone, to devise novel therapeutic strategies to restore CBF in stroke and AD. In brain slices, I found that agonists of Gq protein-coupled receptors (GqPCRs) elevated intracellular pericyte Ca2+ ([Ca2+]i) by triggering Cl- exit via TMEM16A Ca2+-gated Cl- channels. This depolarised pericytes and amplified contraction by opening L-type voltage-gated Ca2+ channels (VGCCs). The pericyte [Ca2+]i rise and contraction were reduced by removing extracellular Ca2+, inhibiting TMEM16A channels or removing the depolarising Cl- gradient across the cell membrane. I showed that rodent and human capillary pericytes express TMEM16A highly. Using in vivo two-photon imaging and laser Doppler flowmetry in a mouse model of AD, I found that pericytes constrict capillaries at their somata, where most circumferential processes are located. Constriction to amyloid beta in cerebral slices occurred by a mechanism dependent on endothelin-gated GqPCR activation causing a depolarisation-evoked Ca2+ influx via L-type VGCCs. Blocking VGCCs relaxed pericytes and improved CBF in AD mice. In a mouse model of stroke, TMEM16A block reduced the ischaemia-evoked pericyte Ca2+ influx and improved CBF. The contributions to reducing blood flow of neutrophils (which stalled near pericyte somata), Ca2+-independent modes of constriction and pericyte interactions with microglia were investigated. Overall, my data suggest that TMEM16A channels and VGCCs interact to control pericyte tone and constitute novel therapeutic targets in stroke and AD.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Regulation of cerebral blood flow in health, stroke and Alzheimer’s disease |
| Event: | UCL (University College London) |
| Language: | English |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10126404 |
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