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Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in cerebral small vessels of patients with COVID-19 and elucidate potential mechanisms underlying the vascular pathology. In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. We obtained evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (M pro ) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, M pro induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood–brain barrier due to NEMO ablation. Importantly, a pharmacological inhibitor of RIPK signaling prevented the M pro -induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19. A novel study led by scientists in Lübeck, Germany, shows that SARS-CoV-2-infected brain endothelial cells undergo cell death due to the cleavage of NEMO by the viral protease M pro , potentially causing cerebral COVID-19 and ‘long COVID’ symptoms.

Carbon dioxide (CO₂), the major product of metabolism, has a strong impact on cerebral blood vessels, a phenomenon known as cerebrovascular reactivity. Several vascular risk factors such as hypertension or diabetes dampen this response, making cerebrovascular reactivity a useful diagnostic marker for incipient vascular pathology, but its functional relevance, if any, is still unclear. Here, we found that GPR4, an endothelial H⁺ receptor, and endothelial Gαq/11 proteins mediate the CO₂/H⁺ effect on cerebrovascular reactivity in mice. CO₂/H⁺ leads to constriction of vessels in the brainstem area that controls respiration. The consequential washout of CO₂, if cerebrovascular reactivity is impaired, reduces respiration. In contrast, CO₂ dilates vessels in other brain areas such as the amygdala. Hence, an impaired cerebrovascular reactivity amplifies the CO₂ effect on anxiety. Even at atmospheric CO₂ concentrations, impaired cerebrovascular reactivity caused longer apneic episodes and more anxiety, indicating that cerebrovascular reactivity is essential for normal brain function. The site-specific reactivity of vessels to CO₂ is reflected by regional differences in their gene expression and the release of vasoactive factors from endothelial cells. Our data suggest the central nervous system (CNS) endothelium as a target to treat respiratory and affective disorders associated with vascular diseases.

Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in cerebral small vessels of patients with COVID-19 and elucidate potential mechanisms underlying the vascular pathology. In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. We obtained evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (M ) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, M induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood-brain barrier due to NEMO ablation. Importantly, a pharmacological inhibitor of RIPK signaling prevented the M -induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.

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 Gαq/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 Gαq/11 proteins, such as endothelial NO synthase (eNOS) activity are discussed in cSVD, we wondered whether the brain endothelial Gαq/11 signalling pathway might influence cSVD-related pathology. Methods: Here, we generated mice carrying a brain endothelial-specific deletion of the Gαq/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 Gαq/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, a deletion of the Gαq/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 Gαq/11 in endothelial cells in ageing. Furthermore, our results show that the combination of cerebral endothelial dysfunction and ageing accelerates cognitive impairment.Competing Interest StatementThe authors have declared no competing interest.Footnotes* - three main figures added - six supplemental figures added - text revised - ten co-authors added