Brain endothelial Gα_q/11 signalling in cerebrovascular function and cognition of aged mice

Background: Cerebral small vessel disease (cSVD) is a major cause of stroke and dementia, and is associated with increased blood–brain barrier permeability, neuroinflammation, and endothelial dysfunction. Endothelial Gα_q/11 proteins are involved in vascular tone regulation and have been shown to affect capillary blood flow in the brain. Since factors downstream of activated Gα_q/11 proteins, such as endothelial NO synthase (eNOS) activity, are discussed in cSVD, we asked whether the brain endothelial Gα_q/11 signalling pathway might influence cSVD-related pathology. Methods: Here, we generated mice carrying a brain endothelial-specific deletion of the Gα_q/11 signalling and characterised these mice using different imaging and staining techniques, as well as behaviour tests measuring cognition in adult and aged mice. Immunoblots, electrophysiology, perfusion measurements, and in vitro experiments complemented those techniques. Findings: The brain endothelial Gα_q/11 signalling pathway preserves normal vascular reactivity, and its loss resembles mild endothelial dysfunction in the brain. While the vessel structure was maintained in adult mice, deletion of Gα_q/11 signalling led to capillary rarefaction and blood–brain barrier disruption in aged mice. These effects were accompanied by disturbed VEGF signalling and an increase in senescence markers and oxidative stress in the vasculature, culminating in cognitive impairment with increased tau phosphorylation in the cortex and hippocampus and decreased myelination in the white matter. Interpretation: These findings reflect the main hallmarks of cSVD and demonstrate a protective role of Gα_q/11 in endothelial cells in ageing. Furthermore, our results show that the combination of cerebral endothelial dysfunction and ageing accelerates cognitive impairment. Funding: Research was supported by grants from the European Research Council, the Deutsche Forschungsgemeinschaft, the institutional priority program MI-VascAD of the University of Lübeck, and the Marie-Sklodowska-Curie European Union's Horizon 2020 research program.