Endothelial dysfunction in the Dp16 Down syndrome mouse model

Background: Trisomy 21 (T21) leads to Down syndrome (DS), which is marked by profound alterations in central nervous system (CNS) function. A near constant activation of the interferon response is characteristic of DS as the interferon gene receptor cluster is triplicated in DS due to its location on human chromosome 21. Various CNS irregularities in DS have been linked to the neurovascular unit, with new findings indicating endothelial dysfunction related to the overactive interferon response and subsequent chronic inflammation. We examined vascular impairments in DS using the only transgenic mouse model reflecting the overactive interferon response, combined with ex vivo and in vivo approaches to study the reactivity of intracerebral arterioles. Aim: To explore the cellular and molecular mechanisms underlying DS, with a particular focus on investigating whether the Dp16 mouse model exhibits endothelial cell driven functional variations in the regulation of arteriolar diameter. Methods: Brain parenchymal arterioles were isolated from both WT and Dp16 mice cortex to perform pressure myography. We pharmacologically targeted two endothelial-dependent vasodilatory pathways: endothelium-derived hyperpolarization and nitric oxide release (NO). Cranial window implantation surgery was performed for 2-photon live-imaging yielding a readout for vascular tone in both Dp16 and WT cortices. Results: Compared to controls, arterioles from Dp16 mice exhibited reduced basal activity levels of the small- and intermediate-conductance K+ channel by 50% (p< 0.05) as well as lowered nitric oxide synthase activity by 65% (p< 0.01), all of which are responsible for vasodilation. Our observations further revealed that this divergent activity correlates with Dp16 arterioles constricting more to luminal pressure (myogenic tone) as compared to WT counterparts, ex vivo, and in vivo. Conclusions: These physiological differences ultimately lead to a diminished ability of cerebral blood vessels to dilate. Given the critical role of cerebral blood flow regulation for proper brain function, these alterations could have significant contributions to cognitive impairment in DS. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.