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bioRxiv · 10.1101/2020.01.29.924936

Neurovascular Function in a Novel Model of Experimental Atherosclerosis

Shabir, O.·Pendry, B.·Heath, P. R.·Rebollar, M. A.·Howarth, C.·Wharton, S. B.·Berwick, J.·Francis, S. E.
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Abstract

ObjectiveAtherosclerosis is a major risk factor for dementia. The aims of this study were to determine if experimental atherosclerosis leads to altered neurovascular function and causes neurovascular damage. Approach and ResultsWe analysed cerebral blood volume in male C57BL6/J mice injected with an adeno-associated virus (AAV) vector for mutated proprotein convertase subtilisin/kexin type 9 (PCSK9D377Y) fed a Western diet for 35 weeks to induce atherosclerosis (ATH) and 9-12m male wild-type (WT) C57BL/6J. We imaged blood volume responses to sensory stimulation and vascular reactivity gas challenges in the cortex of the brain through a thinned cranial window using 2D-optical imaging spectroscopy (2D-OIS). Neural activity was also recorded with multi-channel electrodes. Stimulation-evoked cortical haemodynamics, in terms of cerebral blood volume, were significantly reduced in ATH mice compared to WT and evoked neural activity was also significantly lower. However, vascular reactivity as assessed by 10% hypercapnia, remained intact in ATH mice. Immunohistochemistry in ATH mice revealed a reduced number of cortical neurons and pericytes in the cortex, but increased astrogliosis. qRT-PCR revealed significantly enhanced TNF & IL1{beta} in ATH mice compared to WT as well as significant upregulation of eNOS. ConclusionSystemic atherosclerosis causes significant neurovascular decline by 9m in atherosclerotic mice characterised by reduced neural activity, associated with loss of neurons and subsequent reduced cortical haemodynamics in response to physiological stimulations. The altered neurovascular function in ATH mice is chiefly mediated by TNF. HighlightsO_LISystemic atherosclerosis leads to significantly reduced stimulus-evoked hemodynamic responses in the cortex by 9m of age in the rAAV8-mPCSK9-D377Y mouse model of atherosclerosis compared to wild-type controls. C_LIO_LIReduced cerebral haemodynamics are related to reduced neural activity in the cortex that could be due to a loss of cortical neurons potentially caused by significant TNFa-mediated neuroinflammation. C_LI

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Shabir, O., Pendry, B., Heath, P. R., Rebollar, M. A., Howarth, C., Wharton, S. B., Berwick, J., Francis, S. E.. 2020-01-30. Neurovascular Function in a Novel Model of Experimental Atherosclerosis. https://doi.org/10.1101/2020.01.29.924936

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