Parenchymal arterioles (PAs) control blood flow to the neurovascular unit that consists of the neurons, glia and capillaries. Epidemiological studies highlight the involvement of PA dysfunction as being a key driver of cerebral small vessel disease, a leading cause of vascular cognitive impairment (VCI). Despite this the structural and functional features of PAs in physiological and pathological models have been largely unexplored. There are no therapeutic interventions to halt the progression of VCI, a spectrum of cognitive disorders with a cerebrovascular origin. Chronic cerebral hypoperfusion (CCH) and hypertension are major risk factors of VCI. Understanding the combined effects of these morbidities on PA structure and function could provide mechanistic insights into VCI and assist in designing therapies for the condition. In cerebral arteries epoxyeicosatrienoic acids (EETs) are potent dilators that modulate neurovascular coupling. Soluble epoxide hydrolase (sEH) rapidly metabolizes EETs to less active metabolites, thus inhibition of sEH is pharmacologically feasible means of enhancing the pleiotropic effects of EETs by increasing their half-life. The present dissertation describes studies to validate and study a clinically relevant model of VCI induced by bilateral common carotid artery stenosis (BCAS) in adult normotensive Wistar Kyoto (WKY) rats and in spontaneously hypertensive stroke prone rats (SHRSP). The working hypothesis was that impaired endothelium dependent dilation and remodeling in PAs after BCAS would accompany cognitive dysfunction in WKY rats (Chapter 2) and SHRSP (Chapter 3). Data are shown as mean ± SEM, Sham vs BCAS. Impaired memory and spatial learning abilities were observed in WKY rats with BCAS. BCAS impaired endothelial function in PAs from WKY rats, as evidenced by reduced carbachol mediated dilation (% dilation at 10-5M: 29.6 ± 8.1 vs -10.2 ± 7.4, p<0.05). In SHRSP with BCAS memory was impaired, however there was no difference in spatial learning abilities. BCAS also impaired endothelial function in PAs from SHRSP (% dilation at 10-5M: 17.5 ±5.3 vs -0.2 ± 2.9, p<0.05). I hypothesized that effects of CCH on cognitive function and PA dilation would be exacerbated in SHRSP. However, Sham SHRSP had impaired spatial learning abilities and PA dilation compared to Sham WKY rats and BCAS did not worsen these impairments. Furthermore, I hypothesized that chronic administration of a sEH inhibitor in SHRSP with BCAS would prevent CCH induced cognitive impairment by preventing endothelium dysfunction, and arteriole remodeling in the PAs (Chapter 4). Inhibition of sEH improved memory function, increased mRNA markers of neuroprotection and improved PA dilatory function (% dilation at 10-5M, BCAS + vehicle vs BCAS + sEH inhibitor: 3.6 ± 2.4 vs 14.9 ± 3.0, p<0.05). These studies suggest that chronic inhibition of sEH prevents CCH induced memory impairment via neuronal and vascular effects.
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