Hirunpattarasilp, Chanawee; (2021) Regulation of pericyte contractility in health and disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Pericytes regulate blood flow by constricting and dilating capillaries, especially in the brain, which requires a controlled supply of oxygen and energy substrates, and where the majority of the vascular resistance is in the capillaries. This thesis explores cerebral pericyte contractility in health and disease. I showed that pericytes can be identified reliably by bright-field imaging and that the pericyte-specific dye Neurotrace 500/525 in fact preferentially labels pericytes on higher capillary branch orders. Raising pericyte [Ca2+]i evokes a maximum capillary constriction near pericyte somata where pericyte circumferential processes originate, but adjustment of capillary wall tone by longitudinal processes of pericytes on higher order capillary branches may also regulate blood flow. In Alzheimer’s disease (AD) pericytes contract and reduce brain blood flow. The involvement of reactive oxygen species in amyloid β (Aβ)-induced pericyte contraction was assessed. I demonstrated that NADPH oxidase 4 (NOX4) and hydroxyl radicals mediate this process. A combination of NOX4 and endothelin A receptor blockers, or C-type natriuretic peptide, prevented Aβ-induced constriction, suggesting therapeutic approaches to AD targeted at pericytes. Hyperoxia often occurs in clinical situations. In rodent and human brain slices, I showed that hyperoxic perfusion causes capillaries to constrict and pericyte [Ca2+]i to increase. In rat but not human pericytes, this process was inhibited by blocking 20-HETE production, suggesting a role of 20-HETE in hyperoxic pericyte contraction. Cerebral blood flow decreases in COVID-19 patients, in which the SARS-CoV-2 virus binds to angiotensin converting enzyme 2 (ACE2). In the brain I showed that ACE2 is mainly expressed in pericytes. I found that the receptor binding domain (RBD) of the SARS-CoV-2 spike protein potentiates the capillary constriction evoked by angiotensin II, by reducing ACE2 activity, leading to more activation of AT1 receptors by angiotensin II. My results suggest that pericytes could play a role in the neurological complications of COVID-19 and that the AT1R blocker losartan might prevent this.

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