Characterisation of a novel rat model of cerebral small vessel disease with endothelial dysfunction and white matter change
Item statusRestricted Access
Embargo end date31/07/2022
Cerebral small vessel disease (SVD) is the leading cause of vascular dementia and triples patients’ risk of stroke. The link between the blood-brain barrier and white matter changes in SVD is poorly understood but understanding this may lead to potential new targets for therapies. An existing rat model of SVD indicates that the underlying cause is not simply hypertension but an inherent dysfunction in endothelial cells of the blood-brain barrier, which causes a maturation block on the oligodendrocytes of the white matter. Previously we showed that this rat model has a homozygous deletion mutation of the flippase ATP11B, which is sufficient to cause endothelial dysfunction, and that single nucleotide polymorphisms in ATP11B are associated with humans with sporadic SVD. To better elucidate the effects of endothelial dysfunction in this disease, this thesis characterises a novel ATP11B knock-out (ATP11BKO) transgenic rat to examine how well it reflects SVD pathology. The ATP11BKO rat will provide a platform to study endothelial dysfunction in the absence of hypertension and may also offer a new model of SVD to trial new approaches to tackling this disease. To demonstrate the importance of ATP11B, initial experiments show ATP11B knockdowns in human endothelial cells, where dysfunction is demonstrated and the maturation block on oligodendrocytes is paralleled. The ATP11BKO animal is shown to be normotensive but to exhibit key features of SVD. Endothelial cell dysfunction is demonstrated with key markers including loss of tight junction marker CLDN5, increased levels of ICAM-1 and reduced vessel lumen size. Next, effects on oligodendroglia are shown by reduced maturation as a direct result of this dysfunction. Furthermore, the scope for the ATP11BKO animal as a model for SVD is suggested by broader white matter changes in vivo. In particular, the difference between young and older animals of this genotype are discussed with relevance to the underpinning mechanism of SVD. Together, this data lays out characterisation of key features of a novel transgenic animal that offers a potentially useful platform for investigating normotensive SVD and endothelial cell dysfunction.