Intracerebral age-independent reduction of endothelium-dependent hyperpolarization and nitric oxide signalling in the Dp16 mouse model of Down syndrome.

Down syndrome (DS) is associated with a myriad of cardiovascular defects. Endothelial cells, which form the innermost layer of blood vessels, have been found to exhibit divergent morphology and functional impairments in the peripheral circulation of individuals with DS. DS is also a strong risk factor for Alzheimer's disease-related neuropathology. Recent evidence linking cerebral vasculature to Alzheimer's disease, along with established correlations between cardiovascular and cognitive functions, prompted us to investigate brain parenchymal microcirculation reactivity in a DS mouse model. We used brain parenchymal arterioles to investigate the impact of DS on endothelium-dependent vasodilatation using the Dp16 mouse model coupled with ex vivo pressure myography and in vivo two-photon laser-scanning microscopy. Two age cohorts of mice, young and middle-aged adults, were employed to test for age dependence, with the imminent development of Alzheimer's disease with age of individuals with DS in mind. Using pressure myography combined with pharmacological inhibitors, we examined two essential vasodilatory pathways in intracerebral arterioles - endothelial nitric oxide synthase and endothelium-dependent hyperpolarization mediated by small- and intermediate-conductance potassium channels. These pathways exhibited reduced constitutive activity in the DS model in both age groups. Consistent with these impairments, we measured higher levels of pressure-induced constriction, also referred to as myogenic tone, in arterioles from the cortex of Dp16 mice seen both in vivo and ex vivo. Together, our findings demonstrate altered cerebrovascular functionality in DS and identify possible therapeutic targets for alleviating symptoms associated with DS. KEY POINTS: Down syndrome is associated with cardiovascular diseases. Endothelium-dependent hyperpolarization and nitric oxide synthase activity are reduced in Dp16 brain parenchymal arterioles. Parenchymal arteriole myogenic tone is elevated in Dp16 mice both ex vivo and in vivo. Endothelial dysfunction is a therapeutic target in Down syndrome. Restoration of cerebral blood flow through vascular modulation may be beneficial.