Kenny, B-AM; (2017) Defining novel mediators and mechanisms of neural microvasculature permeability. Doctoral thesis , UCL (University College London).

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Abstract

The microvasculature of the nervous system is exceptionally specialised and its restrictive nature implied by its moniker, blood-brain barrier (BBB), with blood-retinal barrier (BRB) relating to the retinal vasculature. The importance of these barriers is evident during disease states where their functionality is compromised, as in diabetic retinopathy (DR). Due to the complexity of circulating and local mediators with signalling potential at these barriers, and the lack of adequate treatment for some disorders with microvasculature disturbances, there is scope for enriching the knowledge base in this area. With DR as a starting point, it was hypothesised that there were factors other than vascular endothelial growth factor (VEGF) involved in disease progression. It was shown that a bioactive lipid, lysophosphatidylcholine (LPC), enhanced junctional permeability at both the BBB and BRB, doing so via VEGF receptor 2 (VEGFR2) activation thus implicating a transactivation mechanism. It followed that such a mechanism might be involved in the actions of other vascular mediators, bradykinin (BK), lysophosphatidic acid (LPA), thrombin (THR) and TNF-α, and the data shown suggests that this may be the case for more than one of the mediators tested. The former set of data also indicated the presence of transcellular transport across the BBB, the existence of which is highly contested within the literature, and a subsequent aim, investigating the extent of transcytosis for a range of pertinent mediators, was addressed, and for which novel multicellular BBB models were developed and characterised. Finally, in connection with the vesicular process observed for mediators tested, VE-Cadherin (VEC) internalisation, hypothetically to vesicular structures, was tested following ICAM-1 adhesion, as it is key to leukocyte migration via VEC modulation. This cumulative work demonstrates novel roles for LPC-induced permeability, VEGFR2 transactivation by vasoactive stimuli, transcytosis and VEC internalisation at the BBB.

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